Isoxazoline fibrinogen receptor antagonists

ABSTRACT

This invention relates to novel isoxazolines and isoxazoles of formula (I):                    
     or a pharmaceutically acceptable salt or prodrug form thereof. The invention relates to novel isoxazolines which are useful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogen receptor complex, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of platelet aggregation, as thrombolytics, and/or for the treatment of thromboembolic disorders.

This application claims the benefit of U.S. Provisional Application No.60/108,835, filed Nov. 18,1998.

FIELD OF THE INVENTION

This invention relates to novel isoxazolines and isoxazoles which areuseful as antagonists of the platelet glycoprotein IIb/IIIa fibrinogenreceptor complex, to pharmaceutical compositions containing suchcompounds, processes for preparing such compounds, and to methods ofusing these compounds, alone or in combination with other therapeuticagents, for the inhibition of platelet aggregation, as thrombolytics,and/or for the treatment of thromboembolic disorders.

BACKGROUND OF THE INVENTION

Hemostasis is the normal physiological process in which bleeding from aninjured blood vessel is arrested. It is a dynamic and complex process inwhich platelets play a key role. Within seconds of vessel injury,resting platelets become activated and are bound to the exposed matrixof the injured area by a phenomenon called platelet adhesion. Activatedplatelets also bind to each other in a process called plateletaggregation to form a platelet plug. The platelet plug can stop bleedingquickly, but it must be reinforced by fibrin for long-termeffectiveness, until the vessel injury can be permanently repaired.

Thrombosis may be regarded as the pathological condition whereinimproper activity of the hemostatic mechanism results in intravascularthrombus formation. Activation of platelets and the resulting plateletaggregation and platelet factor secretion has been associated with avariety of pathophysiological conditions including cardiovascular andcerebrovascular thromboembolic disorders, for example, thethromboembolic disorders associated with unstable angina, myocardialinfarction, transient ischemic attack, stroke, atherosclerosis anddiabetes. The contribution of platelets to these disease processes stemsfrom their ability to form aggregates, or platelet thrombi, especiallyin the arterial wall following injury.

Platelets are activated by a wide variety of agonists resulting inplatelet shape change, secretion of granular contents and aggregation.Aggregation of platelets serves to further focus clot formation byconcentrating activated clotting factors at the site of injury. Severalendogenous agonists including adenosine diphosphate (ADP), serotonin,arachidonic acid, thrombin, and collagen, have been identified. Becauseof the involvement of several endogenous agonists in activating plateletfunction and aggregation, an inhibitor which acts against all agonistswould represent a more efficacious antiplatelet agent than currentlyavailable antiplatelet drugs, which are agonist-specific.

Current antiplatelet drugs are effective against only one type ofagonist; these include aspirin, which acts against arachidonic acid;ticlopidine, which acts against ADP; thromboxane A₂ synthetaseinhibitors or receptor antagonists, which act against thromboxane A₂;and hirudin, which acts against thrombin. Additionally, currentantiplatelet drugs effective against platelet glycoprotein IIb/IIIacomplex include Reopro™, Integrilin™, and Aggrastat™.

A common pathway for all known agonists has been identified, namelyplatelet glycoprotein IIb/IIIa complex (GPIIb/IIIa), which is themembrane protein mediating platelet aggregation. A recent review ofGPIIb/IIIa is provided by Phillips et al. Cell (1991) 65: 359-362. Thedevelopment of a GPIIb/IIIa antagonist represents a promising newapproach for antiplatelet therapy.

GPIIb/IIIa does not bind soluble proteins on unstimulated platelets, butGPIIb/IIIa in activated platelets is known to bind four soluble adhesiveproteins, namely fibrinogen, von Willebrand factor, fibronectin, andvitronectin. The binding of fibrinogen and von Willebrand factor toGPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen ismediated in part by the Arg-Gly-Asp (RGD) recognition sequence which iscommon to the adhesive proteins that bind GPIIb/IIIa.

In addition to GPIIb/IIIa, increasing numbers of other cell surfacereceptors have been identified which bind to extracellular matrixligands or other cell adhesion ligands thereby mediating cell-cell andcell-matrix adhesion processes. These receptors belong to a genesuperfamily called integrins and are composed of heterodimerictransmembrane glycoproteins containing α- and β-subunits. Integrinsubfamilies contain a common β-subunit combined with differentα-subunits to form adhesion receptors with unique specificity. The genesfor eight distinct β-subunits have been cloned and sequenced to date.

Two members of the β1 subfamily, α4/β1 and α5/β1 have been implicated invarious inflammatory processes. Antibodies to α4prevent adhesion oflymphocytes to synovial endothelial cells in vitro, a process which maybe of importance in rheumatoid arthritis (VanDinther-Janssen et al., J.Immunol., 1991, 147:4207). Additional studies with monoclonalanti-Q4antibodies provide evidence that α4/β1 may additionally have arole in allergy, asthma, and autoimmune disorders (Walsh et al., J.Immunol., 1991, 146:3419; Bochner et al., J. Exp. Med., 1991 173:1553;Yednock et al., Nature, 1992, 356:63). Anti-α4 antibodies also block themigration of leukocytes to the site of inflammation (Issedutz et al., J.Immunol., 1991, 147:4178).

The α_(v)/β₃ heterodimer, commonly referred to as the vitronectinreceptor, is another member of the β₃ integrin subfamily and has beendescribed in platelets, endothelial cells, melanoma, smooth muscle cellsand on the surface of osteoclasts (Horton and Davies, J. Bone Min. Res.1989, 4:803-808; Davies et al., J. Cell. Biol. 1989, 109:1817-1826;Horton, Int. J. Exp. Pathol., 1990, 71:741-759). Like GPIIb/IIIa, thevitronectin receptor binds a variety of RGD-containing adhesive proteinssuch as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bonesialo protein II and thrombospondin in a manner mediated by the RGDsequence. Possible roles for α_(v)/β₃ in angiogenesis, tumorprogression, and neovascularization have been proposed (Brooks et al.,Science, 1994, 264:569-571). A key event in bone resorption is theadhesion of osteoclasts to the matrix of bone. Studies with monoclonalantibodies have implicated the α_(v)/β₃ receptor in this process andsuggest that a selective av/P3 antagonist would have utility in blockingbone resorption (Horton et al., J. Bone Miner. Res., 1993, 8:239-247;Helfrich et al., J. Bone Miner. Res., 1992, 7:335-343).

Several RGD-peptidomimetic compounds have been reported which blockfibrinogen binding and prevent the formation of platelet thrombi. SeeEuropean Patent Application Publication Number 478363, European PatentApplication Publication Number 478328, and PCT Patent Application9307867, and European Patent Application Publication Number 4512831.

U.S. Pat. No. 5,607,952, published Mar. 4, 1997, discloses fibrinogenreceptor antagonists, wherein the substituted 4-phenylthiazolecontaining compounds of general formula:

are disclosed.

Canadian Patent Application 2,122,571, published Nov. 11, 1994,discloses fibrinogen receptor antagonists, wherein compounds of generalformula:

are disclosed.

Copending commonly assigned U.S. patent application U.S. Ser. No.08/337,920, filed Nov. 10, 1994, Wityak et al. (PCT WO95/14683,published Jun. 1, 1995) discloses compounds having the general formula:

which are useful as IIB/IIIA antagonists. See also related PCTWO96/38426, published Dec. 5, 1996.

Commonly assigned U.S. Pat. No. 5,446,056, issued Aug. 29, 1995,discloses compounds having the general formula:

which are useful as IIB/IIIA antagonists. See also PCT WO96/38426,published Dec. 5, 1996.

Commonly assigned U.S. Pat. No. 5,710,159, issued Jan. 20, 1998,discloses compounds having the general formula:

which are useful as a_(v)b₃ antagonists.

None of the above references teach or suggest the compounds of thepresent invention which are described in detail below.

SUMMARY OF THE INVENTION

The present invention provides novel nonpeptide compounds which bind tointegrin receptors thereby altering cell-matrix and cell-cell adhesionprocesses. The compounds of the present invention are useful for thetreatment of thrombosis, inflammation, bone degradation, tumors,metastases, and cell aggregation-related conditions in a mammal.

One aspect of this invention provides novel compounds of Formula (I)(described below) which are useful as antagonists of the plateletglycoprotein IIb/IIIa complex. The compounds of the present inventioninhibit the binding of fibrinogen to platelet glycoprotein IIb/IIIacomplex and inhibit the aggregation of platelets. The present inventionalso includes pharmaceutical compositions containing such compounds ofFormula (I), and methods of using such compounds for the inhibition ofplatelet aggregation, as thrombolytics, and/or for the treatment ofthromboembolic disorders.

The present invention also includes methods of treating cardiovasculardisease, thrombosis or harmful platelet aggregation, reocclusionfollowing thrombolysis, reperfusion injury, or restenosis byadministering a compound of Formula (I) alone or in combination with oneor more additional therapeutic agents selected from: anti-coagulantssuch as warfarin or heparin; anti-platelet agents such as aspirin,piroxicam or ticlopidine; thrombin inhibitors such as hirudin orargatroban; or thrombolytic agents such as tissue plasminogen activator,anistreplase, urokinase, streptokinase, or reteplase; or combinationsthereof.

The present invention also provides novel compounds, pharmaceuticalcompositions and methods which may be used in the treatment orprevention of diseases which involve cell adhesion processes, including,but not limited to, rheumatoid arthritis, asthma, allergies, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease and otherautoimmune diseases.

Also included in the present invention are pharmaceutical kitscomprising one or more containers containing pharmaceutical dosage unitscomprising a compound of Formula (I), for the treatment of cell adhesionrelated disorders, including but not limited to thromboembolicdisorders.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides novel nonpeptide compounds of Formula (I)(described below) which bind to integrin receptors thereby alteringcell-matrix and cell-cell adhesion processes. The compounds of thepresent invention are useful for the treatment of thrombosis,inflammation, bone degradation, tumors, metastases, and cellaggregation-related conditions in a mammal.

One aspect of this invention provides compounds of Formula (I)(described below) which are useful as antagonists of the plateletglycoprotein IIb/IIIa complex. The compounds of the present inventioninhibit the binding of fibrinogen to the platelet glycoprotein IIb/IIIacomplex and inhibit the aggregation of platelets. The present inventionalso includes pharmaceutical compositions containing such compounds ofFormula (I), and methods of using such compounds for the inhibition ofplatelet aggregation, as thrombolytics, and/or for the treatment ofthromboembolic disorders.

[1] This Invention Relates to Novel Compounds of the Formula (I):

or a pharmaceutically acceptable salt form thereof wherein:

b is a single or double bond;

R¹ is selected from

R^(2a)(R³)N—V—,

R²(R^(2b))N(R³N═)C—V,

R²(R^(2b))N(R³N═)CNH—V—,

R²(R¹¹O)N(R³N═)C—V—,

R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from:

-(C₁-C₄ alkyl)-,

-(C₂-C₄ alkenyl)-,

-(C₂-C₄ alkynyl)-,

-(phenyl)-, said phenyl substituted with 0-2 groups independentlyselected from R⁹,

-(pyridyl)-, said pyridyl substituted with 0-2 groups independentlyselected from R⁹, or

-(pyridazinyl)-, said pyridazinyl substituted with 0-2 groupsindependently selected from R⁹;

Z is selected from: a bond, O, S, S(═O), and S(═O)₂;

R^(2a) is R² or R²(R^(2b))N(R³N═))C—;

R², R^(2b), and R³ are independently selected from:

H, C₁-C₁₀ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,

C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl,

aryl, arylcarbonyl, aryl(C₁-C₄ alkyl)-, diarylmethyl,

2,2-diarylethyl, benzhydryl(C₁-C₄ alkyl)-, heteroaryl,

heteroaryl(C₁-C₅ alkyl)-, and

a cleavable protecting group selected from:

C₁-C₆ alkoxycarbonyl,

C₃-C₁₁ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

(C₃-Cil cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

wherein at least one of R², R^(2b), and R³ is H or a cleavableprotecting group;

wherein said aryl groups of R², R^(2b), and R³ may be substituted with0-3 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, —CN, —SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —SO₂NH₂, —NR²¹R²², C₁-C₄haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and

 said heteroaryl groups of R², R^(2b), and R³ may be substituted with0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, SO₂CH₃, and —NR²¹R²²;

alternatively, R² and R^(2b) can be taken together with the nitrogenatom to which they are attached to form a 5-14 membered heterocyclicring optionally containing one additional heteroatom selected from: N,O, or S; said heterocyclic ring being monocyclic, bicyclic, ortricyclic; said heterocyclic ring being substituted with 0-R⁴;

R⁴, when a substituent on carbon, is independently selected from H,C₁-C₄ alkyl, aryl, aryl(C₁-C₆ alkyl)-, C₁-C₄ alkoxy, halogen,methylenedioxydiyl, (C₁-C₆ alkyl)SO₂NH—, (C₆-C₁₁aryl)SO₂NH—, (C₁-C₆alkyl)CONH—, (C₆-C₁₁ aryl)CONH—, (C₁-C₆ alkyl)NHCO—, (C₆-C₁₁ aryl)NHCO—,(C₁-C₆ alkyl)NHCO—, (C₆-C₁₁ aryl)NHCO—, (C₁-C₆ alkyl)NHSO₂—, (C₆-C₁₁aryl)NHSO₂—, (C₁-C₆ alkyl)SO₂—, (C₆-C₁₁ aryl)SO₂—,

wherein said aryl groups may be optionally substituted with 0-3 groupsselected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, OCF₃,SCH₃, S(O)CH₃, SO₂CH₃, —NR²¹R²², C₁-C₄ haloalkyl, methylenedioxydiyl,and ethylenedioxydiyl;

alternatively, when two R⁴ groups are attached to adjacent carbon atoms,they may be taken together with the atoms to which they are attached toform a fused 5-7 membered saturated, unsaturated or aromatic carbocyclicring;

alternatively, when R⁴ is attached to a saturated carbon atom, it mayalso be ═O or ═S;

R⁴, when a substituent on nitrogen, is independently selected from:

H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₁-C₁₀ alkoxycarbonyl,

C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkylsulfonyl,

C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

C₃-C₁₁ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryl, aryl(C₁-C₁₀ alkyl)-, diarylmethyl,

2,2-diarylethyl, benzhydryl(C₁-C₄ alkyl)-,

arylcarbonyl, aryloxycarbonyl, arylsulfonyl,

aryl(C₁-C₁₀ alkyl)sulfonyl,

aryl(C₂-C₁₀ alkenyl)sulfonyl,

aryl (C₁-C₁₀ alkoxy) carbonyl,

heteroaryl, heteroarylsulfonyl,

heteroarylcarbonyl, heteroaryl(C₁-C₁₀ alkyl)-, and

heteroaryl (C₁-C₁₀ alkyl)carbonyl,

wherein said aryl or heteroaryl groups may be additionally substitututedwith 0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, SCH₃, SOCH₃, SO₂CH₃, or —NR²¹R²²;

R⁴ when a substituent on sulfur, may be ═O;

G is C(R⁷) or N;

X is —CH₂—CH(W^(a))—, —CH(W^(b))—CH₂— or —CH(W^(b))—;

Y is selected from hydroxy,

C₁-C₁₀ alkyloxy,

C₃-C₁₁ cycloalkyloxy,

C₆-C₁₀ aryloxy,

C₇-C₁₁ arylalkyloxy,

C₂-C₁₀ alkylcarbonyloxyalkyloxy,

C₂-C₁₀ alkoxycarbonyloxyalkyloxy,

C₂-C₁₀ alkoxycarbonylalkyloxy,

C₄-C₁₀ cycloalkylcarbonyloxyalkyloxy,

C₄-C₁₀ cycloalkoxycarbonyloxyalkyloxy,

C₄-C₁₀ cycloalkoxycarbonylalkyloxy,

C₇-C₁₁ aryloxycarbonylalkyloxy,

C₇-C₁₂ aryloxycarbonyloxyalkyloxy,

C₇-C₁₂ arylcarbonyloxyalkyloxy,

C₄-C₁₀ alkoxyalkylcarbonyloxyalkyloxy,

(5-(C₁-C₄ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R²⁸) (R²⁹)N—(C₁-C₁₀ alkoxy)-;

W^(a) is selected from:

H, hydroxy, —NR¹⁶R²⁰, —NR²⁵R²⁶, C₁-C₁₀ alkoxy,

C₁-C₁₀ alkyl substituted with 0-3 R⁸, and

aryl substituted with 0-3 R⁸,

W^(b) is selected from:

H, CH₂OH, CH₂OR¹², CH₂CO₂R¹², CH₂C(═O)NHR¹⁸, CH₂NR¹⁶R²⁰, CH₂NR²⁵R²⁶,

C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl,

C₄-C₁₁ cycloalkylmethyl,

C₁-C₈ alkyl substituted with 0-2 R⁸,

aryl substituted with 0-3 R⁸, and

aryl(C₁-C₆ alkyl), said aryl substituted with 0-3 R⁸;

R⁵ is selected from:

H, hydroxy, fluoro, —NH(CH₂)_(s)R⁸, —NH(CH₂)_(s)CO₂R¹²,

—O(CH₂)_(s)CO₂R¹², —NR²⁵R²⁶,

C₁-C₈ alkyl substituted with 0-2 R⁸,

C₁-C₁₀ alkoxy substituted with 0-2 R⁸,

C₃-C₆ alkenyl,

C₄-C₁₁ cycloalkylmethyl, and

aryl(C₁-C₆ alkyl)-;

R⁶ is H, methyl, or fluoro;

alternatively, R⁵ and R⁶ can be taken together to be ═O, ═CHR^(8a) or═CHCH₂R⁸;

R⁷ is selected from: H, hydroxy, —OR¹², —OC(═O)R¹³, —OC(═O)OR¹⁴,—OC(═O)NR²³R²⁴, and —O(CH₂)_(s)CO₂R¹²;

alternatively, when G is C(R⁷), R⁷ and R⁶ may be taken together to forma carbon-carbon double bond;

R^(7a) and R^(7b) are independently selected from H, methyl, ethyl, and═O;

alternatively, when R⁷ and R^(7a) occur on adjacent carbons R⁷ andR^(7a) may be taken together to form a carbon-carbon double bond;

alternatively, when R^(7a) and R^(7b) occur on adjacent carbons R^(7a)and R^(7b) may be taken together to form a six carbon aromatic ring;

R⁸ is selected from:

H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —OC(═O)R¹³,

—OC(═O)OR¹⁴, —OR¹², —OCH₂CO₂R¹², —CO₂CH₂CO₂R¹²,

—OC(═O)NR²³R²⁴, —C(═O)NR²³R²⁴, —NR²⁵R²⁶, —NR²⁷C(═O)R¹³,

—NR²⁷C(═O)OR¹⁴, —NR²⁷SO₂R¹⁴, —SR¹⁴, —SOR¹⁴, —SO₂R₁₄,

—SO₂NR²³R²⁴, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylcarbonyl,

C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl,

C₄-C₁₁ cycloalkylmethyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMeor —NMe₂,

aryl(C₁-C₄ alkyl)-, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe, or —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃,CO₂R¹², SO₂Me, SOMe, SMe or —NMe₂;

R^(8a) is selected from:

H, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴,

C₁-C₁₀ alkylcarbonyl, C₂-C₆ alkenyl,

C₃-C₁₀ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,

halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMe or —NMe₂, and

aryl(C₁-C₄ alkyl)-, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe, or —NMe₂;

R⁹ is selected from H, halogen, CF₃, CN, C₁-C₄ alkyl, or C₁-C₄ alkoxy;

R¹⁰ is selected from:

H, hydroxy, CN, carboxy, —NR²⁵R²⁶; C₁-C₆ alkyl,

C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl,

C₇-C₁₄ bicycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkylthio,

C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl,

C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl,

aryl, piperidinyl, morpholinyl, and pyridinyl;

R¹¹ is selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₄-C₁₁ cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹² is selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl,

aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹³ is selected from:

hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl,

C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,

aryl, aryl(C₁-C₄ alkyl)-, heteroaryl,

heteroaryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹⁴ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₄-C₁₁ cycloalkylmethyl, aryl,

aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹⁵ is selected from:

H, OH, —OR¹², —CO₂R¹², —C(═O)NR²³R²⁴, —OC(═O)NR²³R²⁴,

C₁-C₁₀ alkoxycarbonyl substituted with 0-2 R⁸;

C₁-C₁₀ alkyl substituted with 0-3 R⁸;

C₂-C₁₀ alkenyl substituted with 0-3 R⁸; and

C₁-C₁₀ alkoxy substituted with 0-3 R⁸;

R¹⁶ is selected from:

—C(═O)OR¹⁷, —C(═O)R¹⁸, —C(═O)NR¹⁷R¹⁸, —C(═O)NHSO₂R¹⁷,

—C(═O) NHC(═O)R¹⁷, —C(═O)NHC(═O)OR¹⁷, —C(═O)NHSO₂NHR¹⁷,

—SO₂R¹⁷, —SO₂NR¹⁷R¹⁸, and —SO₂NHC(═O)OR¹⁷;

R¹⁷ is selected from:

C₁-C₈ alkyl substituted with 0-2 R¹⁹,

C₃-C₈ alkenyl substituted with 0-2 R¹⁹,

C₃-C₈ alkynyl substituted with 0-2 R¹⁹,

C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹, aryl substituted with 0-4R¹⁹,

aryl (C₁-C₆ alkyl)- substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selectedindependently from O, S, and N, said heterocyclic ring being substitutedwith 0-4 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemhaving 1-3 heteroatoms selected independently from O, S, and N, saidheterocyclic ring being substituted with 0-4 R¹⁹;

R¹⁸ is selected from H or R¹⁷;

R¹⁹ is selected from: H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶,

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,

C₃-C₁₁ cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-,

aryl, aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl;

R²⁰ is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-,

aryl, and aryl(C₁-C₁₀ alkyl)-;

R²¹ and R²² are each independently H, methyl, ethyl, propyl, or butyl;

R²³ is selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₄-C₁₁ cycloalkylmethyl, hydroxy, C₁-C₆ alkoxy,

benzyloxy, aryl, aryl(C₁-C₄ alkyl)-, heteroaryl,

heteroaryl(C₁-C₄ alkyl)-, adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R²⁴ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl,

C₄-Cil cycloalkylmethyl, aryl,

aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R²⁵ and R²⁶ are, independently, selected from:

H, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxycarbonyl,

C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkylsulfonyl,

aryl, aryl(C₁-C₄ alkyl)-, arylcarbonyl,

aryloxycarbonyl, arylsulfonyl,

aryl (C₁-C₁₀ alkoxy) carbonyl,

aryl(C₁-C₁₀ alkyl)sulfonyl,

aryl(C₂-C₁₀ alkenyl)sulfonyl,

C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,

C₃-C₁₀ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

heteroaryl, heteroarylcarbonyl,

heteroarylsulfonyl, and

heteroaryl(C₁-C₄ alkyl)carbonyl,

wherein said aryl groups are optionally substituted with 1-3substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and NO₂;

R²⁷ is selected from H, methyl, ethyl, propyl, butyl, benzyl, phenethyl,cyclopropyl, and cyclopropylmethyl;

R²⁸ and R²⁹ are independently selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl),aryl(CO-C₄ alkyl), and heteroaryl(C₀-C₄ alkyl),

wherein said aryl or heteroaryl groups are substituted with 0-2substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, F,Cl, Br, CF₃, and NO₂;

n is 0, 1, or 2;

q is 1, 2, 3, or 4;

r is 0, 1, or 2; and

s is 1, 2, 3, or 4.

[2] A first Embodiment of This Invention Provides Compounds of Formula(Ia):

or a pharmaceutically acceptable salt form thereof wherein:

b is a single or double bond;

R¹ is selected from

R^(2a)(R³)N—V—,

R^(2a)(R³)N(CH₂)_(q)—,

R²(R^(2b))N(R³N═)C—V—,

R²(R^(2b))N(R³N═)C(CH₂)_(q)—,

R²(R^(2b))N(R³N═)CNH—V—,

R²(R¹¹O)N(R³N═)C—V—,

R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from:

-(C₁-C₄ alkyl)-,

-(C₂-C₄ alkenyl)-,

-(C₂-C₄ alkynyl)-,

-(phenyl)-, said phenyl substituted with 0-2 groups independentlyselected from R⁹,

-(pyridyl)-, said pyridyl substituted with 0-2 groups independentlyselected from R⁹, or

-(pyridazinyl)-, said pyridazinyl substituted with 0-2 groupsindependently selected from R⁹;

Z is selected from: a bond, O, S, S(═O), and S(═O)₂;

R^(2a) is R² or R²(R^(2b))N(R³N═)C—;

R², R^(2b), and R³ are independently selected from:

H, C₁-C₁₀ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl, aryl,arylcarbonyl,

aryl(C₁-C₄ alkyl)-, diarylmethyl, 2,2-diarylethyl,

benzhydryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₅ alkyl)-, and

a cleavable protecting group selected from:

C₁-C₆ alkoxycarbonyl,

C₃-C₁₁ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

(C₃-C₁₁ cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

wherein at least one of R², R^(2b), and R³ is H or a cleavableprotecting group;

wherein said aryl groups of R², R^(2b), and R³ may be substituted with0-3 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, —CN, —SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —SO₂NH₂, —NR²¹R²², C₁-C₄haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and

 said heteroaryl groups of R², R^(2b), and R³ may be substituted with0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, SO₂CH₃, and —NR²¹R²²;

alternatively, R² and R^(2b) can be taken together with the nitrogenatom to which they are attached to form a 5-14 membered heterocyclicring optionally containing one additional heteroatom selected from: N,O, or S; said heterocyclic ring being monocyclic, bicyclic, ortricyclic; said heterocyclic ring being substituted with 0-3 R⁴;

R⁴, when a substituent on carbon, is independently selected from H,C₁-C₄ alkyl, aryl, aryl(C₁-C₆ alkyl)-,

C₁-C₄ alkoxy, halogen, methylenedioxydiyl,

(C₁-C₆ alkyl)SO₂NH—, (C₆-C₁₁ aryl)SO₂NH—,

(C₁-C₆ alkyl)CONH—, (C₆-C₁₁ aryl)CONH—,

(C₁-C₆ alkyl)NHCO—, (C₆-C₁₁ aryl)NHCO—,

(C₁-C₆ alkyl)NHSO₂—, (C₆-C₁₁ aryl)NHSO₂—,

(C₁-C₆ alkyl)SO₂—, (C₆-Cli aryl)SO₂—,

wherein said aryl groups may be optionally substituted with 0-3 groupsselected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, OCF₃,SCH₃, S(O)CH₃, SO₂CH₃, —NR²¹R²², C₁-C₄ haloalkyl, methylenedioxydiyl,and ethylenedioxydiyl;

alternatively, when two R⁴ groups are attached to adjacent carbon atoms,they may be taken together with the atoms to which they are attached toform a fused 5-7 membered saturated, unsaturated or aromatic carbocyclicring;

alternatively, when R⁴ is attached to a saturated carbon atom, it mayalso be ═O or ═S;

R⁴ when a substituent on nitrogen, is independently selected from: H,C₁-C₆ alkyl, C₃-C₆ alkenyl,

C₁-C₁₀ alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl,

C₁-C₁₀ alkylsulfonyl, C₃-C₁₀ cycloalkyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, C₃-C₁₁ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl,

aryl, aryl(C₁-C₁₀ alkyl)-, diarylmethyl,

2,2-diarylethyl, benzhydryl(C₁-C₄ alkyl)-,

arylcarbonyl, aryloxycarbonyl, arylsulfonyl, aryl(C₁-C₁₀ alkyl)sulfonyl,aryl(C₂-C₁₀ alkenyl)sulfonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl, heteroaryl,

heteroarylsulfonyl, heteroarylcarbonyl, heteroaryl(C₁-C₁₀ alkyl)-, andheteroaryl(C₁-C₁₀ alkyl)carbonyl,

wherein said aryl or heteroaryl groups may be additionally substitututedwith 0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, SCH₃, SOCH₃, SO₂CH₃, or —NR²¹R²²;

R⁴ when a substituent on sulfur, may be ═O;

X is —CH₂—CH(W^(a))—, —CH(W^(b))—CH₂— or —CH(W^(b))—;

Y is selected from hydroxy,

C₁-C₁₀ alkyloxy,

C₃-C₁₁ cycloalkyloxy,

C₆-C₁₀ aryloxy,

C₇-C₁₁ arylalkyloxy,

C₂-C₁₀ alkylcarbonyloxyalkyloxy,

C₂-C₁₀ alkoxycarbonyloxyalkyloxy,

C₂-C₁₀ alkoxycarbonylalkyloxy,

C₄-C₁₀ cycloalkylcarbonyloxyalkyloxy,

C₄-C₁₀ cycloalkoxycarbonyloxyalkyloxy,

C₄-C₁₀ cycloalkoxycarbonylalkyloxy,

C₇-C₁₁ aryloxycarbonylalkyloxy,

C₇-C₁₂ aryloxycarbonyloxyalkyloxy,

C₇-C₁₂ arylcarbonyloxyalkyloxy,

C₄-C₁₀ alkoxyalkylcarbonyloxyalkyloxy,

(5-(C₁-C₄ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R²⁸) (R²⁹)N—(C₁-C₁₀ alkoxy)

W^(a) is selected from:

H, hydroxy, —NR¹⁶R²⁰, —NR²⁵R²⁶, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl substitutedwith 0-3 R⁸, and

aryl substituted with 0-3 R⁸,

W^(b) is selected from: H, CH₂OH, CH₂OR¹², CH₂CO₂R¹²,

CH₂C(═O)NHR¹⁸, CH₂NR¹⁶R²⁰, CH₂NR²⁵R²⁶,

C₃-C₆ alkenyl,

C₃-C₁₀ cycloalkyl,

C₄-C₁₁ cycloalkylmethyl,

C₁-C₈ alkyl substituted with 0-2 R⁸,

aryl substituted with 0-3 R⁸, and

aryl(C₁-C₆ alkyl), said aryl substituted with 0-3 R⁸;

R⁵ is selected from:

H, hydroxy, fluoro, —NH(CH₂)_(s)R⁸, —NH(CH₂)_(s)CO₂R¹²,

—O(CH₂)_(s)CO₂R¹²—NR²⁵R²⁶, and

C₁-C₈ alkyl substituted with 0-2 R⁸,

C₁-C₁₀ alkoxy substituted with 0-2 R⁸,

C₃-C₆ alkenyl,

C₄-C₁₁ cycloalkylmethyl, and

aryl(C₁-C₆ alkyl)-;

R⁶ is H, methyl, or fluoro;

alternatively, R⁵ and R⁶ can be taken together to be ═O, =CHR^(8a) or═CHCH₂R⁸;

R⁷ is selected from:

H, hydroxy, —OR¹², —OC(═O)R¹³, —OC(═O)OR¹⁴,

OC(═O)NR²³R²⁴, and —O(CH₂)_(s)CO₂R¹²;

alternatively, R⁷ and R⁶ may be taken together to form a carbon-carbondouble bond;

R^(7a) and R^(7b) are independently selected from H, methyl, ethyl, and═O;

alternatively, when R⁷ and R^(7a) occur on adjacent carbons R⁷ andR^(7a) may be taken together to form a carbon-carbon double bond;

alternatively, when R^(7a) and R^(7b) occur on adjacent carbons R^(7a)and R^(7b) may be taken together to form a six carbon aromatic ring;

R⁸ is selected from:

H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —OC(═O)R¹³, —OC(═O)OR¹⁴, —OR¹²,—OCH₂CO₂R¹², —CO₂CH₂CO₂R¹², —OC(═O)NR²³R²⁴, —C(═O)NR²³R²⁴, —NR²⁵R²⁶,—NR²⁷C(═O)R¹³, —NR²⁷C(═O)OR¹⁴, —NR²⁷SO₂R¹⁴, —SR¹⁴, —SOR¹⁴, —SO₂R¹⁴,—SO₂NR²³R²⁴, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylcarbonyl, C₂-C₆ alkenyl, C₃-C₁₀cycloalkyl, C₄-C₁₁ cycloalkylmethyl;

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMeor —NMe₂,

aryl(C₁-C₄ alkyl)-, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe, or —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃,CO₂R¹², SO₂Me, SOMe, SMe or —NMe₂;

R^(8a) is selected from:

H, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴, C₁-C₁₀ alkylcarbonyl, C₂-C₆alkenyl, C₃-C₁₀ cycloalkyl, C₄-C₁₁ cycloalkylmethyl;

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMeor —NMe₂, and

aryl(C₁-C₄ alkyl)-, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe, or —NMe2.

R⁹ is selected from H, halogen, CF₃, CN, C₁-C₄ alkyl, or C₁-C₄ alkoxy;

R¹⁰ is selected from:

H, hydroxy, CN, carboxy, —NR²⁵R²⁶, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₇ cycloalkyl, C₇-C₁₄ bicycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aryl, piperidinyl, morpholinyl, andpyridinyl;

R¹¹ is selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substitutedwith 1-2 R¹⁰;

R¹² is selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl, aryl (C₁-C₄ alkyl) -, and C₁-C₁₀ alkylsubstituted with 1-2 R¹⁰;

R¹³ is selected from:

hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-Cli cycloalkyl, C₄-Clicycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹⁴ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,aryl, aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹⁵ is selected from:

H, OH, —OR¹², —CO₂R¹², —C(═O)NR²³R²⁴, —OC(═O)NR²³R²⁴;

C₁-C₁₀ alkoxycarbonyl substituted with 0-2 R⁸;

C₁-C₁₀ alkyl substituted with 0-3 R⁸;

C₂-C₁₀ alkenyl substituted with 0-3 R⁸; and

C₁-C₁₀ alkoxy substituted with 0-3 R⁸;

R¹⁶ is selected from:

—C(═O)OR¹⁷, —C(═O)R¹⁸, —C(═O)NR¹⁷R¹⁸, —C(═O)NHSO₂R¹⁷, —C(═O)NHC(═O)R¹⁷,—C(═O)NHC(═O)OR¹⁷,

—C(═O)NHSO₂NHR¹⁷, —SO₂R¹⁷, —SO₂NR¹⁷R⁸, and —SO₂NHC(═O)OR¹⁷;

R¹⁷ is selected from:

C₁-C₈ alkyl substituted with 0-2 R¹⁹,

C₃-C₈ alkenyl substituted with 0-2 R¹⁹,

C₃-C₈ alkynyl substituted with 0-2 R¹⁹,

C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁-C₆ alkyl)- substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selectedindependently from O, S, and N, said heterocyclic ring being substitutedwith 0-4 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemhaving 1-3 heteroatoms selected independently from O, S, and N, saidheterocyclic ring being substituted with 0-4 R¹⁹;

R¹⁸ is selected from H or R¹⁷;

R¹⁹ is selected from:

H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl;

R²⁰ is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁cycloalkyl(C₁-C₄ alkyl)-, aryl, and aryl(C₁-C₁₀ alkyl)-;

R²¹ and R²² are each independently H, methyl, ethyl, propyl, or butyl;

R²³ is selected from:

hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, hydroxy, C₁-C₆ alkoxy, benzyloxy, aryl, aryl(C₁-C₄alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl)-, adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R²⁴ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,aryl, aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R²⁵ and R²⁶ are, independently, selected from:

H, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀alkylsulfonyl, aryl, aryl(C₁-C₄ alkyl)-, arylcarbonyl, aryloxycarbonyl,arylsulfonyl, aryl(C₁-C₁₀ alkoxy)carbonyl, aryl(C₁-C₁₀ alkyl)sulfonyl,aryl(C₂-C₁₀ alkenyl)sulfonyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₃-C₁₀ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl, heteroaryl, heteroarylcarbonyl,heteroarylsulfonyl, and heteroaryl(C₁-C₄ alkyl)carbonyl,

wherein said aryl groups are optionally substituted with 1-3substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and NO₂;

R²⁷ is selected from H, methyl, ethyl, propyl, butyl, benzyl, phenethyl,cyclopropyl, and cyclopropylmethyl;

R²⁸ and R²⁹ are independently selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl),aryl(C₀-C₄ alkyl), and heteroaryl(C₀-C₄ alkyl), wherein said aryl orheteroaryl groups are substituted with 0-2 substituents independentlyselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂;

n is 0, 1, or 2;

q is 1, 2, 3, or 4;

r is 0, 1, or 2; and

s is 1, 2, 3, or 4.

[3] Preferred Compounds of This First Embodiment are Those of Formula(Ia) wherein:

b is a single or double bond;

R¹ is selected from

R^(2a)(R³)N—V—,

R²(R^(2b))N(R³N═)C—V—,

R²(R^(2b))N(R³N═)CNH—V—,

R²(R¹⁰O)N(R³N═)C—V—,

R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from:

-(C₁-C₄ alkyl)-,

-(phenyl)-, said phenyl substituted with 0-2 groups independentlyselected from R⁹,

-(pyridyl)-, said pyridyl substituted with 0-2 groups independentlyselected from R⁹, or

-(pyridazinyl)-, said pyridazinyl substituted with 0-2 groupsindependently selected from R⁹;

Z is selected from: a bond, O, and S(═O)₂;

W^(a) is selected from:

H, hydroxy, —NHR¹⁶, —NR²⁵R²⁶, C₁-C₁₀ alkoxy,

C₁-C₁₀ alkyl substituted with 0-3 R⁸, and aryl substituted with 0-3 R⁸,

R⁶ is H;

alternatively, R⁵ and R⁶ can be taken together to be ═O, ═CHR^(8a) or═CHCH₂R⁸;

R⁷ is selected from H, hydroxy, —OR¹², and —O(CH₂)_(s)CO₂R¹²;

alternatively, R⁷ and R⁶ may be taken together to form a carbon-carbondouble bond;

R¹² is selected from H, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substitutedwith 1-2 R¹⁰;

R¹⁵ is selected from H, OH, —OR¹², —CO₂R¹², —C(═O)NR²³R²⁴, and—OC(═O)NR²³R²⁴;

R¹⁶ is selected from —C(═O)OR¹⁷, —C(═O)R¹⁸, —SO₂R¹⁷, and —SO₂NR¹⁷R¹⁸;

R¹⁷ is selected from:

C₁-C₈ alkyl substituted with 0-2 R¹⁹,

C₃-C₈ alkenyl substituted with 0-2 R¹⁹,

C₃-C₈ alkynyl substituted with 0-2 R¹⁹,

C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁-C₆ alkyl)- substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl,said heterocyclic ring being substituted with 0-4 R¹⁹, said heterocyclicring being substituted with 0-4 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring beingsubstituted with 0-4 R¹⁹;

R¹⁸ is selected from H or C₁-C₅ alkyl;

n is 0, 1 or 2;

q is 1, 2, 3, or 4;

r is 0, 1, or 2; and

s is 1, 2, 3, or 4.

[4] Further Preferred Compounds of This First Embodiment are Those ofFormula (Ia) Wherein:

b is a single or double bond;

R¹ is selected from

R² (R^(2b))N(R³N═)C—V—,

R²(R^(2b))N(R³N═)CNH—V—,

V is selected from:

-(C₁-C₄ alkyl)-,

-(pyridyl)-, and

-(phenyl)-, said phenyl substituted with 0-2 groups independentlyselected from F, Br, methyl, and methoxy;

Z is a bond or O;

R², R^(2b), and R³ are independently selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl, aryl,arylcarbonyl, aryl(C₁-C₄ alkyl)-, diarylmethyl, 2,2-diarylethyl,benzhydryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl)-, and

a cleavable protecting group selected from:

C₁-C₆ alkoxycarbonyl,

C₃-C₈ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryloxycarbonyl,

aryl(C₁-C₈ alkoxy)carbonyl,

(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

(C₃-C₈ cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

wherein at least one of R², R^(2b), and R³ is H or a cleavableprotecting group;

wherein said aryl groups of R², R^(2b), and R³ may be substituted with0-3 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, —CN, —SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —SO₂NH₂, —NR²¹R²², C₁-C₄haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and

 said heteroaryl groups of R², R^(2b), and R³ may be substituted with0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, SO₂CH₃, and —NR²¹R²²;

alternatively, R² and R^(2b) can be taken together with the nitrogenatom to which they are attached to form a 5-14 membered heterocyclicring system selected from morpholine, piperidine, piperazine,pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine,1,4-benzoxazine, 8-oxo-3-aza-bicyclo[3.2.1]octane,2,6-dimethylmorpholine, 2,6-dimethylpiperazine,1,2,3,4-tetrahydro-2,7—Naphthyridine, 1,4-dioxa-8-azaspiro[4.5]decane,azepine, or 2,3-dihydro-1H-benzo[de]isoquinoline, said heterocyclic ringbeing substituted with 0-2 R⁴;

X is —CH₂—CH(W^(a))— or —CH(W^(b))—;

Y is selected from hydroxy,

hydroxy;

C₁-C₆ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

W^(a) is H or —NHR¹⁶;

W^(b) is selected from H, methyl, ethyl, benzyl, phenethyl, pyridyl,CH₂C(═O)NHR¹⁸, and CH₂NHR¹⁶;

R⁸ is selected from:

H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴, —NR²⁵R²⁶, —SR¹⁴,—SOR¹⁴, —SO₂ ¹⁴, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylcarbonyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMeor —NMe₂,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl,benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl,pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;

R¹⁵ is selected from H, OH, —OR¹², and —OC(═O)NR²³R²⁴;

R¹⁶ is —C(═O)OR¹⁷ or —SO₂R¹⁷;

R¹⁷ is selected from:

C₁-C₈ alkyl,

C₂-C₈ alkenyl,

aryl substituted with 0-4 R¹⁹,

aryl(C₁-C₆ alkyl)- substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl,said heterocyclic ring being substituted with 0-4 R¹⁹, said heterocyclicring being substituted with 0-4 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring beingsubstituted with 0-4 R¹⁹;

R¹⁹ is selected from:

H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl;

n is 1 or 2;

q is 1, 2, 3, or 4;

r is 0, 1, or 2; and

s is 1, 2, 3, or 4.

[5] Further Preferred Compounds of This First Embodiment are Compoundsof Formula (Ia) Wherein:

b is a single bond;

R¹ is R²(R^(2b))N(R³N═)C—V— or R²(R²b)N(R³N═)CNH—V—;

V is -(pyridyl)- or -(phenyl)-, said phenyl substituted with 0-2 groupsindependently selected from F, Br, methyl, and methoxy;

Z is a bond or O;

R², R^(2b), and R³ are independently selected from:

H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl,

C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₄ alkyl)-,

C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl, arylcarbonyl,

aryl(C₁-C₄ alkyl)-, diarylmethyl, 2,2-diarylethyl,

heteroaryl, heteroaryl(C₁-C₄ alkyl)-, and

a cleavable protecting group selected from:

C₁-C₄ alkoxycarbonyl,

C₃-C₆ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryl(C₁-C₈ alkoxy)carbonyl,

(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

(C₃-C₈ cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

wherein at least one of R², R^(2b), and R³ is H or a cleavableprotecting group;

wherein said aryl groups of R², R^(2b), and R³ may be substituted with0-3 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy,butoxy, methyl, ethyl, propyl, butyl, CF₃, —CN, —SO₂(CH₃), —SO₂(C₂H₅),—SO₂(C₃H₇), —SO₂(C₄H₉), —SO₂NH₂, —NR²¹R²², C₁-C₄ haloalkyl,methylenedioxydiyl, and ethylenedioxydiyl; and

 said heteroaryl groups of R², R^(2b), and R³ may be substituted with0-2 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy,butoxy, methyl, ethyl, propyl, butyl, CF₃, SO₂CH₃, and —NR²¹R²²;

alternatively, R² and R^(2b) can be taken together with the nitrogenatom to which they are attached to form a 5-14 membered heterocyclicring system selected from morpholine, piperidine, piperazine,pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine,1,4-benzoxazine, 8-oxo-3-aza-bicyclo[3.2.1]octane,2,6-dimethylmorpholine, 2,6-dimethylpiperazine,1,2,3,4-tetrahydro-2,7—Naphthyridine, 1,4-dioxa-8-azaspiro[4.5]decane,azepine, or 2,3-dihydro-1H-benzo[de]isoquinoline, said heterocyclic ringbeing substituted with 0-2 R⁴;

R⁴, when a substituent on carbon, is independently selected from H, F,Cl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, methylenedioxydiyl,—NH₂, —NHSO₂CH₃, —NHSO₂C₂H₅, —NHSO₂C₃H₇, —NHSO₂ (phenyl), —NHC(═O)CH₃,—NHC(═O)C₂H₅, and phenyl;

wherein said phenyl groups may be optionally substituted with 0-3 groupsselected from hydroxy, halogen, methoxy, methyl, ethyl, CF₃, SCH₃, —NH₂,—NH(CH₃), —N(CH₃)₂, methylenedioxydiyl, and ethylenedioxydiyl;

alternatively, when two R⁴ groups are attached to adjacent carbon atoms,they may be taken together with the atoms to which they are attached toform a fused 5-7 membered saturated, unsaturated or aromatic carbocyclicring;

alternatively, when R⁴ is attached to a saturated carbon atom, it mayalso be ═O or ═S;

R⁴ when a substituent on nitrogen, is independently selected from H,methyl, ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, phenyl,phenylmethyl, phenylethyl, pyridyl, pyridylmethyl

wherein said phenyl or pyridyl groups may be additionally substitututedwith 0-2 groups selected from hydroxy, halogen, methoxy, methyl, ethyl,CF₃, SCH₃, —NH₂, —NH(CH₃), and —N(CH₃)₂;

R⁴ when a substituent on sulfur, may be ═O;

X is —CH₂—CH(W^(a))— or —CH(W^(b))—;

Y is selected from hydroxy; methoxy; ethoxy; isopropoxy;

n-butyloxy; isobutyloxy; t-butoxy; benzyloxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-l,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

W^(a) is H or —NHR¹⁶;

W^(b) is H, methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl,CH₂C(═O)NHR¹8, and CH₂NHR¹⁶;

R⁸ is selected from:

H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴, —NR²⁵R²⁶, —SR¹⁴,—SOR¹⁴, —SO₂R¹⁴, C₁-C₄ alkoxy, C₁-C₄ alkylcarbonyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl,CF₃, CO₂R¹², SO₂Me, SOMe, SMe or —NMe₂,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl,benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl,pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;

R¹⁵ is H;

R¹⁶ is —SO₂R¹⁷, —C(═O)OCH₂CH₂CH₂CH₃, —C(═O)OCH₂CH(CH₃)₂ or—C(═O)OCH₂(C₆H₅);

R¹⁷ is selected from:

C₁-C₈ alkyl,

aryl substituted with 0-2 R¹⁹,

aryl(C₁-C₆ alkyl)- substituted with 0-2 R¹⁹,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl,said heterocyclic ring being substituted with 0-2 R¹⁹, said heterocyclicring being substituted with 0-2 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring beingsubstituted with 0-2 R¹⁹;

R¹⁹ is selected from:

H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₄ alkyl)-, C₁-C₄ alkoxy, and C₁-C₄ alkoxycarbonyl;

n is 1; and

s is 1 or 2.

[6] Specifically Preferred Compounds of This First Embodiment areCompounds, or Pharmaceutically Acceptable Salt or Prodrug Forms Thereof,Selected From:

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl-methyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(2-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-hydroxypiperidin-1-yl]aceticacid,

3-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl-methyl]-4-hydroxypiperidin-1-yl]propionicacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl-methyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(2-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl-methyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl-methyl]-4-(2-carboxyethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl-methyl]piperidin-1-yl]aceticacid,

3-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-yl-methyl]piperidin-1-yl]propionicacid,

2-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(phenylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(n-propylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(ethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(piperidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(thiazolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-phenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(pyrrolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydro-2,7—Naphthyridino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(thiomorpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(2-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-propylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2-fluorophenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-(carboxymethoxy)piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(phenylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(n-propylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(ethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(piperidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(thiazolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-phenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(pyrrolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2,3,4,5-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(thiomorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(2-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(4-propylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2-fluorophenylpiperazino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-[3,6]-dihydro-2H-pyridin-1-yl]aceticacid,

2-[4-[3-[4-(n-butylaminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-[3,6]-dihydro-2H-pyridin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-[3,6]-dihydro-2H-pyridin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[3,6]-dihydro-2H-pyridin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-[3,6]-dihydro-2H-pyridin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[3,6]-dihydro-2H-pyridin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[3,6]-dihydro-2H-pyridin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethylene]-piperidin-1-yl]aceticacid,

2-[4-[3-[4-(n-butylaminoiminomethyl)phenyl]isoxazolin-5-ylmethylene]-piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethylene]-piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethylene]-piperidin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethylene]-piperidin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethylene]-piperidin-1-yl]aceticacid, and

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethylene]-piperidin-1-yl]aceticacid.

[7] Further Preferred Compounds of This First Embodiment are Those ofFormula (Ia) Wherein the Stereochemistry of the Isoxazolin-5-ylmethylMoiety is Isoxazolin-5(S)-ylmethyl.

[8] Further Preferred Compounds of This First Embodiment are Those ofFormula (Ia) Wherein the Stereochemistry of the Isoxazolin-5-ylmethylMoiety is Isoxazolin-5(R)-ylmethyl.

[9] A Second Embodiment of This Invention Provides a Compound of Formula(Ib):

or a pharmaceutically acceptable salt form thereof wherein:

b is a single or double bond;

R¹ is selected from

R^(2a)(R³)N—V—,

R^(2a)(R³)N(CH₂)_(q)—,

R²(R^(2b))N(R³N═)C—V—,

R²(R^(2b))N(R³N═))C(CH₂)_(q)—,

R²(R^(2b))N(R³N═)CNH—V—,

R²(R¹¹O)N(R³N═)C—V—,

R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from:

-(C₁-C₄ alkyl)-,

-(C₂-C₄ alkenyl)-,

-(C₂-C₄ alkynyl)-,

-(phenyl)-, said phenyl substituted with 0-2 groups independentlyselected from R⁹,

-(pyridyl)-, said pyridyl substituted with 0-2 groups independentlyselected from R⁹, or

-(pyridazinyl)-, said pyridazinyl substituted with 0-2 groupsindependently selected from R⁹;

Z is selected from: a bond, O, S, S(═O), and S(═O)₂;

R^(2a) is R² or R²(R^(2b))N(R³N═)C—;

R², R^(2b), and R³ are independently selected from:

H, C₁-C₁₀ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl, aryl,arylcarbonyl, aryl(C₁-C₄ alkyl)-, diarylmethyl, 2,2-diarylethyl,benzhydryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₅ alkyl)-, and

a cleavable protecting group selected from:

C₁-C₆ alkoxycarbonyl,

C₃-C₁₁ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryloxycarbonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl,

(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

(C₃-C₁₁ cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

wherein at least one of R², R^(2b), and R³ is H or a cleavableprotecting group;

wherein said aryl groups of R², R^(2b), and R³ may be substituted with0-3 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, —CN, —SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —SO₂NH₂, —NR²¹R²², C₁-C₄haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and

 said heteroaryl groups of R², R^(2b), and R³ may be substituted with0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, SO₂CH₃, and —NR²lR²²;

alternatively, R² and R²b can be taken together with the nitrogen atomto which they are attached to form a 5-14 membered heterocyclic ringoptionally containing one additional heteroatom selected from: N, O, orS; said heterocyclic ring being monocyclic, bicyclic, or tricyclic; saidheterocyclic ring being substituted with 0-3 R⁴;

R⁴, when a substituent on carbon, is independently selected from H,C₁-C₄ alkyl, aryl, aryl(C₁-C₆ alkyl)-,

C₁-C₄ alkoxy, halogen, methylenedioxydiyl,

(C₁-C₆ alkyl)SO₂NH—, (C₆-C₁₁ aryl)SO₂NH—,

(C₁-C₆ alkyl)CONH—, (C₆-C₁₁ aryl)CONH—,

(C₁-C₆ alkyl)NHCO—, (C₆-C₁₁ aryl)NHCO—,

(C₁-C₆ alkyl)NHSO₂—, (C₆-C₁₁ aryl)NHSO₂—,

(C₁-C₆ alkyl)SO₂—, (C₆-C₁₁ aryl)SO₂—,

wherein said aryl groups may be optionally substituted with 0-3 groupsselected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, OCF₃,SCH₃, S(O)CH₃, SO₂CH₃, —NR²¹R²², C₁-C₄ haloalkyl, methylenedioxydiyl,and ethylenedioxydiyl;

alternatively, when two R⁴ groups are attached to adjacent carbon atoms,they may be taken together with the atoms to which they are attached toform a fused 5-7 membered saturated, unsaturated or aromatic carbocyclicring;

alternatively, when R⁴ is attached to a saturated carbon atom, it mayalso be ═O or ═S;

R⁴, when a substituent on nitrogen, is independently selected from H,C₁-C₆ alkyl, C₃-C₆ alkenyl, C₁-C₁₀ alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl,

C₁-C₁₀ alkylsulfonyl, C₃-C₁₀ cycloalkyl,

C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, C₃-C₁₁ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl,

aryl, aryl(C₁-C₁₀ alkyl)-, diarylmethyl,

2,2-diarylethyl, benzhydryl(C₁-C₄ alkyl)-,

arylcarbonyl, aryloxycarbonyl, arylsulfonyl, aryl(C₁-C₁₀ alkyl)sulfonyl,aryl(C₂-C₁₀ alkenyl)sulfonyl,

aryl(C₁-C₁₀ alkoxy)carbonyl, heteroaryl,

heteroarylsulfonyl, heteroarylcarbonyl, heteroaryl(C₁-C₁₀ alkyl)-, andheteroaryl(C₁-C₁₀ alkyl)carbonyl,

wherein said aryl or heteroaryl groups may be additionally substitututedwith 0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, SCH₃, SOCH₃, SO₂CH₃, or —NR²¹R²²;

R⁴ when a substituent on sulfur, may be ═O;

X is —CH₂—CH(W^(a))—, —CH(W^(b))—CH₂— or —CH(W^(b))—;

Y is selected from hydroxy,

C₁-C₁₀ alkyloxy,

C₃-C₁₁ cycloalkyloxy,

C₆-C₁₀ aryloxy,

C₇-C₁₁ arylalkyloxy,

C₂-C₁₀ alkylcarbonyloxyalkyloxy,

C₂-C₁₀ alkoxycarbonyloxyalkyloxy,

C₂-C₁₀ alkoxycarbonylalkyloxy,

C₄-C₁₀ cycloalkylcarbonyloxyalkyloxy,

C₄-C₁₀ cycloalkoxycarbonyloxyalkyloxy,

C₄-C₁₀ cycloalkoxycarbonylalkyloxy,

C₇-C₁₁ aryloxycarbonylalkyloxy,

C₇-C₁₂ aryloxycarbonyloxyalkyloxy,

C₇-C₁₂ arylcarbonyloxyalkyloxy,

C₄-C₁₀ alkoxyalkylcarbonyloxyalkyloxy,

(5-(C₁-C₄ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,

(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and

(R²⁸) (R²⁹)N—(C₁-C₁₀ alkoxy)-;

W^(a) is selected from:

H, hydroxy, —NR¹⁶R²⁰, —NR²⁵R²⁶, C₁-C₁₀ alkoxy,

C₁-C₁₀ alkyl substituted with 0-3 R⁸, and

aryl substituted with 0-3 R⁸,

W^(b) is selected from:

H, CH₂OH, CH₂OR¹², CH₂CO₂R¹², CH₂C(═O)NHR¹⁸, CH₂NR¹⁶R²⁰,

CH₂NR²⁵R²⁶, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,pyridyl; and

C₁-C₈ alkyl substituted with 0-2 R⁸;

aryl substituted with 0-3 R⁸; and

aryl(C₁-C₆ alkyl), said aryl substituted with 0-3 R⁸;

R⁵ is selected from:

H, C₃-C₆ alkenyl, C₄-C₁₁ cycloalkylmethyl, aryl(C₁-C₆ alkyl)-, and C₁-C₈alkyl substituted with 0-2 R⁸,

R⁶ is H or methyl;

alternatively, R⁵ and R⁶ can be taken together to be ═O;

R^(7a) and R^(7b) are independently selected from H, methyl, ethyl, and═O;

alternatively, when R^(7a) and R^(7b) occur on adjacent carbons R^(7a)and R^(7b) may be taken together to form a six carbon aromatic ring;

R⁸ is selected from:

H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —OC(═O)R¹³, —oc(═O)OR¹⁴, —OR¹²,—OCH₂CO₂R¹², —CO₂CH₂CO₂R¹², —OC(═O)NR²³R²⁴, —C(═O)NR²³R²⁴, —NR²⁵R²⁶,—NR²⁷C(═O)R¹³, —NR²⁷C (═O) OR¹⁴, —NR²⁷SO₂R¹⁴, —SR¹⁴, —SOR¹⁴, —SO₂R¹⁴,—SO₂NR²³R²⁴, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylcarbonyl, C₂-C₆ alkenyl, C₃-C₁₀cycloalkyl, C₄-C₁₁ cycloalkylmethyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMeor —NMe₂,

aryl(C₁-C₄ alkyl)—, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe, or —NMe₂, and

a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms,wherein said heterocyclic ring may be saturated, partially saturated, orfully unsaturated, said heterocyclic ring being substituted with 0-2groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃,CO₂R¹², SO₂Me, SOMe, SMe or —NMe₂;

R^(8a) is selected from:

H, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴, C₁-C₁₀ alkylcarbonyl, C₂-C₆alkenyl, C₃-C₁₀ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMeor —NMe₂, and

aryl(C₁-C₄ alkyl)-, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe, or —NMe₂.

R⁹ is selected from H, halogen, CF₃, CN, C₁-C₄ alkyl, or C₁-C₄ alkoxy;

R¹⁰ is selected from:

H, hydroxy, CN, carboxy, —NR²⁵R²⁶; C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₇ cycloalkyl, C₇-C₁₄ bicycloalkyl, C₁-C₆ alkoxy, C₁-C₆alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aryl, piperidinyl, morpholinyl, andpyridinyl;

R¹¹ is selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-Cl,cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹² is selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹³ is selected from:

hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₄alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹⁴ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,aryl, aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R¹⁵ is selected from:

H, OH, —OR¹², —CO₂R¹², —C(═O)NR²³R²⁴, —OC(═O)NR²³R²⁴,

C₁-C₁₀ alkoxycarbonyl substituted with 0-2 R⁸;

C₁-C₁₀ alkyl substituted with 0-3 R⁸;

C₂-C₁₀ alkenyl substituted with 0-3 R⁸; and

C₁-C₁₀ alkoxy substituted with 0-3 R⁸;

R¹⁶ is selected from:

—C(═O)OR¹⁷, —C(═O)R¹⁸, —C(═O)NR¹⁷R¹⁸, —C(═O)NHSO₂R¹⁷, —C(═O)NHC(═O)R¹⁷,—C(═O)NHC(═O)OR¹⁷, —C(═O)NHSO₂NHR¹⁷, —SO₂R¹⁷—SO₂NR¹⁷R¹⁸, and—SO₂NHC(═O)OR¹⁷;

R¹⁷ is selected from:

C₁-C₈ alkyl substituted with 0-2 R¹⁹,

C₃-C₈ alkenyl substituted with 0-2 R¹⁹,

C₃-C₈ alkynyl substituted with 0-2 R¹⁹,

C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁-C₆ alkyl)- substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system having 1-3 heteroatoms selectedindependently from O, S, and N, said heterocyclic ring being substitutedwith 0-4 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemhaving 1-3 heteroatoms selected independently from O, S, and N, saidheterocyclic ring being substituted with 0-4 R¹⁹;

R¹⁸ is selected from H or R¹⁷;

R¹⁹ is selected from:

H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl;

R²⁰ is selected from:

H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁cycloalkyl(C₁-C₄ alkyl)-, aryl, and aryl(C₁-C₁₀ alkyl)-;

R²¹ and R²² are each independently H, methyl, ethyl, propyl, or butyl;

R²³ is selected from:

hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, hydroxy, C₁-C₆ alkoxy, benzyloxy, aryl, aryl(C₁-C₄alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl)-, adamantylmethyl, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R²⁴ is selected from:

C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl,aryl, aryl(C₁-C₄ alkyl)-, and

C₁-C₁₀ alkyl substituted with 1-2 R¹⁰;

R²⁵ and R²⁶ are, independently, selected from:

H, C₁-C₁₀ alkyl, C₁-C₁₀ alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀alkylsulfonyl, aryl, aryl(C₁-C₄ alkyl)-, arylcarbonyl, aryloxycarbonyl,arylsulfonyl, aryl(C₁-C₁₀ alkoxy)carbonyl, aryl(C₁-C₁₀ alkyl)sulfonyl,aryl(C₂-C₁₀ alkenyl)sulfonyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₃-C₁₀ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl, heteroaryl, heteroarylcarbonyl,heteroarylsulfonyl, and heteroaryl(C₁-C₄ alkyl)carbonyl,

wherein said aryl groups are optionally substituted with 1-3substituents selected from the group consisting of: C₁-C₄ alkyl, C₁-C₄alkoxy, halo, CF₃, and NO₂;

R²⁷ is selected from H, methyl, ethyl, propyl, butyl, benzyl, phenethyl,cyclopropyl, and cyclopropylmethyl;

R²⁸ and R²⁹ are independently selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀ cycloalkyl(C₀-C₄ alkyl),aryl(C₀-C₄ alkyl), and heteroaryl(C₀-C₄ alkyl), wherein said aryl orheteroaryl groups are substituted with 0-2 substituents independentlyselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, F, Cl, Br, CF₃, and NO₂;

n is 0, 1, or 2;

q is 1, 2, 3, or 4;

r is 0, 1, or 2; and

s is 1, 2, 3, or 4.

[10] Preferred Compounds of This Second Embodiment are Those Compoundsof Formula (Ib) Wherein:

b is a single or double bond;

R¹ is selected from

R^(2a)(R³)N—V—,

R²(R^(2b))N(R³N═)C—V—,

R²(R^(2b))N(R³N═)CNH—V—,

R²(R¹⁰)N(R³N═)C—V—,

R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from:

-(C₁-C₄ alkyl)-,

-(phenyl)-, said phenyl substituted with 0-2 groups independentlyselected from R⁹,

-(pyridyl)-, said pyridyl substituted with 0-2 groups independentlyselected from R⁹, or

-(pyridazinyl)-, said pyridazinyl substituted with 0-2 groupsindependently selected from R⁹;

Z is selected from: a bond, O, and S(═O)₂;

W^(a) is selected from:

H, hydroxy, —NHR¹⁶, —NR²⁵R²⁶, C₁-C₁₀ alkoxy,

C₁-C₁₀ alkyl substituted with 0-3 R⁸, and

aryl substituted with 0-3 R⁸,

R⁶ is H;

alternatively, R⁵ and R⁶ can be taken together to be ═O;

R^(7a) and R^(7b) are independently H or ═O;

R¹² is selected from H, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substitutedwith 1-2 R¹⁰;

R¹⁵ is selected from: H, OH, —OR¹², —CO₂R¹², —C(═O)NR²³R²⁴, and—OC(═O)NR²³R²⁴;

R¹⁶ is selected from —C(═O)OR¹⁷, —C(═O)R¹⁸, —SO₂R¹⁷, and —SO₂NR¹⁷R¹⁸;

R¹⁷ is selected from:

C₁-C₈ alkyl substituted with 0-2 R¹⁹,

C₃-C₈ alkenyl substituted with 0-2 R¹⁹,

C₃-C₈ alkynyl substituted with 0-2 R¹⁹,

C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹,

aryl substituted with 0-4 R¹⁹,

aryl(C₁-C₆ alkyl)- substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl,said heterocyclic ring being substituted with 0-4 R¹⁹, said heterocyclicring being substituted with 0-4 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring beingsubstituted with 0-4 R¹⁹;

R¹⁸ is selected from H or C₁-C₅ alkyl;

n is 0, 1 or 2;

q is 1, 2, 3, or 4;

r is 0, 1, or 2; and

s is 1, 2, 3, or 4.

[11] Further Preferred Compounds of This Second Embodiment are ThoseCompounds of Formula (Ib) Wherein:

b is a single or double bond;

R¹ is selected from

R²(R^(2b))N(R³N═)C—V—,

R²(R^(2b))N(R³N═)CNH—V—,

V is selected from:

-(C₁-C₄ alkyl)-,

-(pyridyl)-, and

-(phenyl)-, said phenyl substituted with 0-2 groups independentlyselected from F. Br, methyl, and methoxy;

Z is a bond or O;

R², R^(2b), and R³ are independently selected from:

H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl, aryl,arylcarbonyl, aryl(C₁-C₄ alkyl) -, diarylmethyl, 2,2-diarylethyl,benzhydryle(C₁-C₄ alkyl)-, heteroaryl, heteroaryl (C-C₄ alkyl)-, and

a cleavable protecting group selected from:

C₁-C₆ alkoxycarbonyl,

C₃-C₈ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryloxycarbonyl,

aryl(C₁-C₈ alkoxy) carbonyl,

(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy (C₁-C₄ alkoxy)carbonyl, and

(C₃-C₈ cycloalkyl)carbonyloxy(C₄-C₄ alkoxy)carbonyl,

wherein at least one of R², R^(2b), and R³ is H or a cleavableprotecting group;

wherein said aryl groups of R², R^(2b), and R³ may be substituted with0-3 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, —CN, —SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —SO₂NH₂, —NR²¹R²², C₁-C₄haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and

 said heteroaryl groups of R², R^(2b), and R³ may be substituted with0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl,CF₃, SO₂CH₃, and —NR²¹R²²;

alternatively, R² and R^(2b) can be taken together with the nitrogenatom to which they are attached to form a 5-14 membered heterocyclicring system selected from morpholine, piperidine, piperazine,pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine,1,4-benzoxazine, 8-oxo-3-aza-bicyclo[3.2.1]octane,2,6-dimethylmorpholine, 2,6-dimethylpiperazine,1,2,3,4-tetrahydro-2,7—Naphthyridine, 1,4-dioxa-8-azaspiro[4.5]decane,azepine, or 2,3-dihydro-1H-benzo[de]isoquinoline, said heterocyclic ringbeing substituted with 0-3 R⁴;

X is —CH₂—CH(W^(a))— or —CH(W^(b))—;

Y is selected from hydroxy,

hydroxy;

C₁-C₆ alkoxy;

methylcarbonyloxymethoxy-;

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

W^(a) is H or —NHR¹⁶;

R⁶ is H;

alternatively, R⁵ and R⁶ can be taken together to be ═O;

R^(7a) and R^(7b) are independently H or ═O;

W^(b) is selected from:

H, methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl,CH₂C(═O)NHR¹⁸, and CH₂NHR¹⁶;

R⁸ is selected from:

H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴, NR²⁵R²⁶, —SR¹⁴,—SOR¹⁴, —SO₂R¹⁴, C₁-C₁₀ alkoxy, C₁-C₁₀ alkylcarbonyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, halo, CF₃, CO₂R¹², SO₂Me, SOMe, SMeor —NMe₂,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl,benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl,pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;

R¹⁵ is selected from H, OH, —OR₁₂, and —OC(═O)NR²³R²⁴;

R¹⁶ is —C(═O)OR¹⁷ or —SO₂R¹⁷;

R¹⁷ is selected from:

C₁-C₈ alkyl,

C₂-C₈ alkenyl,

aryl substituted with 0-4 R¹⁹,

aryl(C₁-C₆ alkyl)-substituted with 0-4 R¹⁹,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl,said heterocyclic ring being substituted with 0-4 R¹⁹, said heterocyclicring being substituted with 0-4 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring beingsubstituted with 0-4 R¹⁹;

R¹⁹ is selected from:

H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl;

n is 1 or 2;

q is 1, 2, 3, or 4;

r is 0, 1, or 2; and

s is 1, 2, 3, or 4.

[12] Further Preferred Compounds of This Second Embodiment are Compoundsof Formula (Ib), Wherein:

b is a single;

R¹ is R²(R^(2b))N(R³N═)C—V— or R²(R²b)N(R³N═)CNH—V—;

V is -(pyridyl)- or -(phenyl)-, said phenyl substituted with 0-2 groupsindependently selected from F, Br, methyl, and methoxy;

Z is a bond or O;

R², R^(2b), and R³ are independently selected from:

H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₈ cycloalkyl, C₃-C₈cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl,arylcarbonyl, aryl(C₁-C₄ alkyl)-, diarylmethyl, 2,2-diarylethyl,heteroaryl, heteroaryl(C₁-C₄ alkyl)-, and

a cleavable protecting group selected from:

C₁-C₄ alkoxycarbonyl,

C₃-C₆ cycloalkoxycarbonyl,

C₇-C₁₁ bicycloalkoxycarbonyl,

aryl(C₁-C₈ alkoxy)carbonyl,

(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and

(C₃-C₈ cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,

wherein at least one of R², R^(2b), and R³ is H or a cleavableprotecting group;

wherein said aryl groups of R², R^(2b), and R³ may be substituted with0-3 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy,butoxy, methyl, ethyl, propyl, butyl, CF₃, —CN, —SO₂(CH₃), —SO₂(C₂H₅),—SO₂(C₃H₇), —SO₂(C₄H₉), —SO₂NH₂, —NR²¹R²², C₁-C₄ haloalkyl,methylenedioxydiyl, and ethylenedioxydiyl; and

 said heteroaryl groups of R², R^(2b), and R³ may be substituted with0-2 groups selected from hydroxy, halogen, methoxy, ethoxy, propoxy,butoxy, methyl, ethyl, propyl, butyl, CF₃, SO₂CH₃, and —NR²¹R²²;

alternatively, R² and R²b can be taken together with the nitrogen atomto which they are attached to form a 5-14 membered heterocyclic ringsystem selected from morpholine, piperidine, piperazine, pyrrolidine,tetrahydroisoquinoline, thiazolidine, thiomorpholine, 1,4-benzoxazine,8-oxo-3-aza-bicyclo[3.2.1]octane, 2,6-dimethylmorpholine,2,6-dimethylpiperazine, 1,2,3,4-tetrahydro-2,7—Naphthyridine,1,4-dioxa-8-azaspiro[4.5]decane, azepine, or2,3-dihydro-1H-benzo[de]isoquinoline, said heterocyclic ring beingsubstituted with 0-2 R⁴;

R⁴, when a substituent on carbon, is independently selected from H, F,Cl, methyl, ethyl, propyl, butyl, methoxy, ethoxy, methylenedioxydiyl,—NH₂, —NHSQ₂CH₃, —NHSO₂C₂H₅, —NHSO₂C₃H₇, —NHSO₂(phenyl), —NHC(═O)CH₃,—NHC(═O)C₂H₅, and phenyl;

wherein said phenyl groups may be optionally substituted with 0-3 groupsselected from hydroxy, halogen, methoxy, methyl, ethyl, CF₃, SCH₃, —NH₂,—NH(CH₃), —N(CH₃)₂, methylenedioxydiyl, and ethylenedioxydiyl;

alternatively, when two R⁴ groups are attached to adjacent carbon atoms,they may be taken together with the atoms to which they are attached toform a fused 5-7 membered saturated, unsaturated or aromatic carbocyclicring;

alternatively, when R⁴ is attached to a saturated carbon atom, it mayalso be ═O or ═S;

R⁴ when a substituent on nitrogen, is independently selected from: H,methyl, ethyl, propyl, butyl, cyclopropyl, cyclopropylmethyl, phenyl,phenylmethyl, phenylethyl, pyridyl, pyridylmethyl

wherein said phenyl or pyridyl groups may be additionally substitututedwith 0-2 groups selected from hydroxy, halogen, methoxy, methyl, ethyl,CF₃, SCH₃, —NH₂, —NH(CH₃), and —N(CH₃)₂;

R⁴ when a substituent on sulfur, may be ═O;

X is —CH₂—CH(W^(a))— or —CH(W^(b))—;

Y is selected from

hydroxy; methoxy; ethoxy; isopropoxy; n-butyloxy;

isobutyloxy; t-butoxy; benzyloxy;

methylcarbonyloxymethoxy

ethylcarbonyloxymethoxy-;

t-butylcarbonyloxymethoxy-;

cyclohexylcarbonyloxymethoxy-;

1-(methylcarbonyloxy)ethoxy-;

1-(ethylcarbonyloxy)ethoxy-;

1-(t-butylcarbonyloxy)ethoxy-;

1-(cyclohexylcarbonyloxy)ethoxy-;

i-propyloxycarbonyloxymethoxy-;

t-butyloxycarbonyloxymethoxy-;

1-(i-propyloxycarbonyloxy)ethoxy-;

1-(cyclohexyloxycarbonyloxy)ethoxy-;

1-(t-butyloxycarbonyloxy)ethoxy-;

dimethylaminoethoxy-;

diethylaminoethoxy-;

(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;

(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;

1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-;

W^(a) is H or —NHR¹⁶;

R⁶ is H;

alternatively, R⁵ and R⁶ can be taken together to be ═O;

R^(7a) and R^(7b) are independently H or ═O;

W^(b) is H, methyl, ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl,CH₂C (═O)NHR¹⁸, and CH₂NHR¹⁶;

R⁸ is selected from:

H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴, —NR²⁵R²⁶, —SR¹⁴,—SOR¹⁴, —SO₂R¹⁴, C₁-C₄ alkoxy, C₁-C₄ alkylcarbonyl,

aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl, propyl, butyl,CF₃, CO₂R¹², SO₂Me, SOMe, SMe or —NMe₂,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, inolinyl, quinolinyl, isoquinolinyl,benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, 3H-indolyl,pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl or morpholinyl;

R¹⁵ is H;

R¹⁶ is —SO₂R¹⁷, —C(═O)OCH₂CH₂CH₂CH₃, —C(═O)OCH₂CH(CH₃)₂ or—C(═O)OCH₂(C₆H₅);

R¹⁷ is selected from:

C₁-C₈ alkyl,

aryl substituted with 0-2 R¹⁹,

aryl(C₁-C₆ alkyl)- substituted with 0-2 R¹⁹,

a 5-10 membered heterocyclic ring system selected from pyridinyl,furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl,said heterocyclic ring being substituted with 0-2 R¹⁹, said heterocyclicring being substituted with 0-2 R¹⁹, and

C₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,pyrrolidinyl, morpholinyl, or piperazinyl, said heterocyclic ring beingsubstituted with 0-2 R¹⁹;

R¹⁹ is selected from:

H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₄ alkyl, C₂-C₄ alkenyl, C₂-C₄alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₄ alkyl)-, C₁-C₄ alkoxy, and C₁-C₄ alkoxycarbonyl;

n is 1; and

s is 1 or 2.

[13] Specifically Preferred Compounds of This First Embodiment areCompounds, or Pharmaceutically Acceptable Salt or Prodrug Forms Thereof,Selected From:

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(phenylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(n-propylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(ethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(piperidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(thiazolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(4-phenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(pyrrolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydro-2,7—Naphthyridino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,4-dioxa-8-azaspiro[4.5]decyl)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(4-(2-fluorophenyl)piperazino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(4-(2-methylphenyl)piperazino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(thiomorpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[2-(2-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(4-propylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(4-benzylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyllisoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazol-5-ylmethyllpiperazin-1-yllaceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,

2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,

2-[4-[3-(1-aminoiminomethylpiperidin-4-yl)-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[(N-methyl-N-phenethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-(4-benzylaminoiminomethylphenyl)-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-(2,2-diphenylethylamino)iminomethylphenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[2-(3-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-(3-pyridylmethylamino)iminomethylphenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[2-(4-chlorophenylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[2-(imidazol-4-ylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[2-(4-aminosulfonylphenylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[2-(4-fluorophenylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[2-(4-methoxyphenylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-(2-indanoiminomethyl)-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,

2-[4-[3-[4-[(4-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(3,4-methylenedioxy-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(6,7-dimethoxy-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[⁴-[³-[⁴-[(⁶-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(8-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(7-chloro-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(5-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(7-fluoro-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(7-methylsulfonylamino-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(5-methylsulfonylamino-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(7-phenylsulfonylamino-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(5-acetylamino-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,

2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid, and

2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid.

[14] Further Preferred Compounds of This Second Embodiment are Those ofFormula (Ia) Wherein the Stereochemistry of the Isoxazolin-5-ylmethylMoiety is Isoxazolin-5(S )-ylmethyl.

[15] Further Preferred Compounds of This Second Embodiment are Those ofFormula (Ia) Wherein the Stereochemistry of the Isoxazolin-5-ylmethylMoiety is Isoxazolin-5(R )-ylmethyl.

In another preferred embodiment, the present invention provides acompound of Formula (Ia) or (Ib) wherein the stereochemistry of theisoxazolin-5-ylmethyl moiety is either isoxazolin-5(S )-ylmethyl orisoxazolin-5(R)-ylmethyl. Depending on the substitution pattern of theisoxazoline, a compound of Formula (Ia) or (Ib) with aisoxazolin-5(S)-ylmethyl or isoxazolin-5(R)-ylmethyl moiety is depictedby one of the following formulas:

In a third embodiment the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of Formula (I) or apharmaceutically acceptable salt form thereof.

In a fourth embodiment the present invention provides a method ofinhibiting the aggregation of blood platelets which comprisesadministering to a host in need of such inhibition a therapeuticallyeffective amount of a compound of Formula (I).

In a fifth embodiment the present invention provides a method oftreating thrombosis, inflammation, bone degradation, tumor, metastasis,or a cell aggregation-related condition which comprises administering toa host in need of such treatment a therapeutically effective amount of acompound of Formula (I).

In a sixth embodiment the present invention provides a method oftreating rheumatoid arthritis, asthma, allergy, adult respiratorydistress syndrome, graft versus host disease, organ transplantation,septic shock, psoriasis, czema, contact dermatitis, osteoporosis,osteoarthritis, atherosclerosis, metastasis, wound healing, diabeticretinopathy, inflammatory bowel disease or other autoimmune diseasewhich comprises administering to a host in need of such treatment atherapeutically effective amount of a compound of Formula (I).

In a seventh embodiment the present invention provides a method oftreating thromboembolic disorders selected from thrombus or embolusformation, harmful platelet aggregation, reocclusion followingthrombolysis, reperfusion injury, restenosis, atherosclerosis, strokemyocardial infarction, and unstable angina, which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of Formula (I).

In an eighth embodiment the present invention provides a method oftreating thromboembolic disorders selected from thrombus or embolusformation, harmful platelet aggregation, reocclusion followingthrombolysis, reperfusion injury, restenosis, atherosclerosis, strokemyocardial infarction, and unstable angina, which comprisesadministering, in combination, to a host in need thereof atherapeutically effective amount of:

(a) a compound of Formula (I); and,

(b) at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.

In the present invention it has been discovered that the compounds ofFormula (I) above are useful as inhibitors of cell-matrix and cell-celladhesion processes. The present invention includes novel compounds ofFormula (I) and methods for using such compounds for the prevention ortreatment of diseases resulting from abnormal cell adhesion to theextracellular matrix which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of such compound ofFormula I.

In the present invention it has also been discovered that the compoundsof Formula (I) above are useful as inhibitors of glycoprotein IIb/IIIa(GPIIb/IIIa). The compounds of the present invention inhibit theactivation and aggregation of platelets induced by all known endogenousplatelet agonists.

The present invention also provides pharmaceutical compositionscomprising a compound of Formula (I) and a pharmaceutically acceptablecarrier.

The compounds of Formula (I) of the present invention are useful for thetreatment (including prevention) of thromboembolic disorders. The term“thromboembolic disorders” as used herein includes conditions involvingplatelet activation and aggregation, such as arterial or venouscardiovascular or cerebrovascular thromboembolic disorders, including,for example, thrombosis, unstable angina, first or recurrent myocardialinfarction, ischemic sudden death, transient ischemic attack, stroke,atherosclerosis, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary and cerebral arterialthrombosis, myocardial infarction, cerebral embolism, kidney embolisms,pulmonary embolisms, or such disorders associated with diabetes,comprising administering to a mammal in need of such treatment atherapeutically effective amount of a compound of Formula (I) describedabove.

The compounds of Formula (I) of the present invention may be useful forthe treatment or prevention of other diseases which involve celladhesion processes, including, but not limited to, infammation, bonedegradation, rheumatoid arthritis, asthma, allergies, adult respiratorydistress syndrome, graft versus host disease, organ transplantationrejection, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, tumors, metastasis,diabetic retinopathy, inflammatory bowel disease and other autoimmunediseases. The compounds of Formula (I) of the present invention may alsobe useful for wound healing.

The compounds of the present invention are useful for inhibiting thebinding of fibrinogen to blood platelets, inhibiting aggregation ofblood platelets, treating thrombus formation or embolus formation, orpreventing thrombus or embolus formation in a mammal. The compounds ofthe invention may be used as a medicament for blocking fibrinogen fromacting at its receptor site in a mammal.

Compounds of the invention may be administered to patients whereprevention of thrombosis by inhibiting binding of fibrinogen to theplatelet membrane glycoprotein complex IIb/IIIa receptor is desired.They are useful in surgery on peripheral arteries (arterial grafts,carotid endarterectomy) and in cardiovascular surgery where manipulationof arteries and organs, and/or the interaction of platelets withartificial surfaces, leads to platelet aggregation and consumption, andwhere the aggregated platelets may form thrombi and thromboemboli. Thecompounds of the present invention may be administered to these surgicalpatients to prevent the formation of thrombi and thromboemboli.

Extracorporeal circulation is routinely used during cardiovascularsurgery in order to oxygenate blood. Platelets adhere to surfaces of theextracorporeal circuit. Adhesion is dependent on the interaction betweenGPIIb/IIIa on the platelet membranes and fibrinogen adsorbed to thesurface of the extracorporeal circuit. Platelets released fromartificial surfaces show impaired homeostatic function. The compounds ofthe invention may be administered to prevent such ex vivo adhesion.

The compounds of the present invention may be used for other ex vivoapplications to prevent cellular adhesion in biological samples.

Other applications of these compounds include prevention of plateletthrombosis, thromboembolism, and reocclusion during and afterthrombolytic therapy and prevention of platelet thrombosis,thromboembolism and reocclusion after angioplasty of coronary and otherarteries and after coronary artery bypass procedures. The compounds ofthe present invention may also be used to prevent myocardial infarction.The compounds of the present invention are useful as thrombolytics forthe treatment of thromboembolic disorders.

The compounds of the present invention can also be administered incombination with one or more additional therapeutic agents select from:anti-coagulant or coagulation inhibitory agents, such as heparin orwarfarin; anti-platelet or platelet inhibitory agents, such as aspirin,piroxicam, or ticlopidine; thrombin inhibitors such as boropeptides,hirudin or argatroban; or thrombolytic or fibrinolytic agents, such asplasminogen activators, anistreplase, urokinase, streptokinase, orreteplase.

The compounds of Formula (I) of the present invention can beadministered in combination with one or more of the foregoing additionaltherapeutic agents, thereby to reduce the doses of each drug required toachieve the desired therapeutic effect. Thus, the combination treatmentof the present invention permits the use of lower doses of eachcomponent, with reduced adverse, toxic effects of each component. Alower dosage minimizes the potential of side effects of the compounds,thereby providing an increased margin of safety relative to the marginof safety for each component when used as a single agent. Suchcombination therapies may be employed to achieve synergistic or additivetherapeutic effects for the treatment of thromboembolic disorders.

The term “integrin” as used herein refers to any of the many cellsurface receptor proteins, also referred to as adhesion proteinreceptors, which have been identified which bind to extracellular matrixligands or other cell adhesion protein ligands thereby mediatingcell-cell and cell-matrix adhesion processes. The integrins are encodedby genes belonging to a gene superfamily and are typically composed ofheterodimeric transmembrane glycoproteins containing α- and β-subunits.Integrin subfamilies contain a common β-subunit combined with differentα-subunits to form adhesion protein receptors with differentspecificities.

The integrin glycoprotein IIb/IIIa (referred to herein as GPIIb/IIIa orIIb/IIIa or the fibrinogen receptor) is the membrane protein mediatingplatelet aggregation. GPIIb/IIIa in activated platelets is known to bindfour soluble RGD-containing adhesive proteins, namely fibrinogen, vonWillebrand factor, fibronectin, and vitronectin. In addition toGPIIb/IIIa, a number of other integrin cell surface receptors have beenidentified, for example, αv β3and α5β1.

The term “integrin antagonists” as referred to herein (also referred toherein as integrin inhibitors) includes compounds (includingpeptidomimetic compounds and other small molecule compounds) which actas inhibitors of the binding of the integrin protein to endogenousprotein ligands of such integrin. Preferred integrin inhibitors used inthe present invention are RGD-peptidomimetic compounds. As used herein,the term “RGD-peptidomimetic compounds” refers to chemical compoundswhich bind to the RGD-binding region of the integrin and which blockRGD-mediated binding of one or more adhesive proteins to such integrin.Preferred in the present invention are antagonists of the avp3 andGPIIb/IIIa integrin.

By “therapeutically effective amount” it is meant an amount of acompound of Formula (I) that when administered alone or in combinationwith an additional therapeutic agent to a cell or mammal is effective toprevent or ameliorate the thromboembolic disease condition or theprogression of the disease. Such disease conditions or diseases includethromboembolic disorders and cell adhesion prosesses as disclosedherein.

By “administered in combination” or “combination therapy” it is meantthat the compound of Formula (I) and one or more additional therapeuticagents are administered concurrently to the mammal being treated. Whenadministered in combination each component may be administered at thesame time or sequentially in any order at different points in time.Thus, each component may be administered separately but sufficientlyclosely in time so as to provide the desired therapeutic effect.

The term “anti-coagulant agents” (or coagulation inhibitory agents), asused herein, denotes agents that inhibit blood coagulation. Such agentsinclude warfarin (available as CoumadinTM), heparin, and low molecularweight heparin.

The term “anti-platelet agents” (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function such as byinhibiting the aggregation, adhesion or granular secretion of platelets.Such agents include the various known non-steroidal anti-inflammatorydrugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac,indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, andpiroxicam, including pharmaceutically acceptable salts or prodrugsthereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), andpiroxicam are preferred. Piroxicam is commercially available from PfizerInc. (New York, N.Y.), as Feldane™. Other suitable anti-platelet agentsinclude ticlopidine, including pharmaceutically acceptable salts orprodrugs thereof. Ticlopidine is also a preferred compound since it isknown to be gentle on the gastro-intestinal tract in use. Still othersuitable platelet inhibitory agents include other IIb/IIIa antagonists,such as ReoPro™ (abciximab, available from Centocor), Integrilin™(eptifibatide, available from COR Therapeutics), and Aggrastat™(tirofiban, available from Merck and Co.).

Still other suitable platelet inhibitory agents includethromboxane-A2-receptor antagonists and thromboxane-A2-synthetaseinhibitors, as well as pharmaceutically acceptable salts or prodrugsthereof.

The phrase “thrombin inhibitors” (or “anti-thrombin agents”), as usedherein, denotes inhibitors of the serine protease thrombin and otherinhibitors of thrombin synthesis such as factor Xa inhibitors. Byinhibiting thrombin, various thrombin-mediated processes, such asthrombin-mediated platelet activation (that is, for example, theaggregation of platelets, and/or the granular secretion of plasminogenactivator inhibitor-1 and/or serotonin) and/or fibrin formation aredisrupted. Such inhibitors include hirudin and argatroban, includingpharmaceutically acceptable salts and prodrugs thereof. The termhirudin, as used herein, includes suitable derivatives or analogs ofhirudin, referred to herein as hirulogs, such as disulfatohirudin.

The term “factor Xa inhibitor”, as used herein, denotes inhibitors offactor Xa, whose major practical role is the generation of thrombin bythe limited proteolysis of prothrombin. The generation of thrombin fromits precursor prothrombin is amplified by formation of prothrombinasecomplex (factor Xa, factor V, Ca²⁺ and phospholipid). Therefore, it isenvisioned that adminstration of an inhibitor of thrombin synthesis,such as a factor Xa inhibitor, in combination therapy with a IIb/IIIainhibitor of the instant invention may be an additional method intreating cardiovascular disease, thrombosis, reocclusion followingthrombolysis, reperfusion injury, or restenosisother than administeringa compound of Formula (I) alone. Such factor Xa inhibitors include, butare not limited to, DX-9065a (Daiichi), ORG31540 (Organon ), SANORG32701 (Sanofi/Organon), and BX-807834 (Berlex). Such factor Xainhibitors also include, but are not limited to, compounds disclosed inWO97/23212, published Jul. 3, 1997; WO97/38984, published Oct. 23, 1997;WO97/30971, published Aug. 28, 1997; WO98/01428, published Jan. 15,1998; WO98/06694, published Feb. 19, 1998; WO98/28269, published Jul. 2,1998; and WO98/28282, published Jul. 2, 1998; each reference hereinincorporated by reference in its entirety.

The phrase “thrombolytic agents” or “fibrinolytic agents” (or“thrombolytics” or “fibrinolytics”), as used herein, denotes agents thatlyse blood clots (thrombi). Such agents include tissue plasminogenactivator, anistreplase, urokinase, streptokinase, or reteplase,including pharmaceutically acceptable salts or prodrugs thereof. Tissueplasminogen activator (tPA) is commercially available from GenentechInc., South San Francisco, California. The term anistreplase, as usedherein, refers to anisoylated plasminogen streptokinase activatorcomplex, as described, for example, in European Patent Application No.028,489, the disclosures of which are hereby incorporated herein byreference herein, in their entirety. Anistreplase is commerciallyavailable as Eminase™. The term urokinase, as used herein, is intendedto denote both dual and single chain urokinase, the latter also beingreferred to herein as prourokinase. Reteplase is manufactured byBoehringer Mannheim Corp. and commercially available as Retavase™.

Administration of the compounds of Formula (I) of the invention incombination with such additional therapeutic agent, may afford anefficacy advantage over the compounds and agents alone, and may do sowhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the binding of fibrinogen to plateletGPIIb/IIIa. Such compounds may be provided in a commercial kit, forexample, for use in pharmaceutical research involving GPIIb/IIIa. Thecompounds of the present invention may also be used in diagnostic assaysinvolving platelet GPIIb/IIIa.

The compounds herein described may have asymmetric centers. Unlessotherwise indicated, all chiral, diastereomeric and racemic forms areincluded in the present invention. Many geometric isomers of olefins,C═N double bonds, and the like can also be present in the compoundsdescribed herein, and all such stable isomers are contemplated in thepresent invention. It will be appreciated that compounds of the presentinvention that contain asymmetrically substituted carbon atoms may beisolated in optically active or racemic forms. It is well known in theart how to prepare optically active forms, such as by resolution ofracemic forms or by synthesis, from optically active starting materials.All chiral, diastereomeric, racemic forms and all geometric isomericforms of a structure are intended, unless the specific stereochemistryor isomer form is specifically indicated.

When any variable (for example but not limited to, R², R^(2b), R⁸, R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁹, R²¹, R²², R²³, R²⁴, R²⁵, R²⁶, and s, etc.)occurs more than one time in any constituent or in any formula, itsdefinition on each occurrence is independent of its definition at everyother occurrence. Thus, for example, if a group is shown to besubstituted with 0-2 R⁸, then said group may optionally be substitutedwith up to two R⁸ and R⁸ at each occurrence is selected independentlyfrom the defined list of possible R⁸.

When a bond to a substituent is shown to cross the bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a bond joining a substituent to another group is notspecifically shown or the atom in such other group to which the bondjoins is not specifically shown, then such substituent may form a bondwith any atom on such other group.

When a substituent is listed without indicating the atom via which suchsubstituent is bonded to the rest of the compound of Formula I, thensuch substituent may be bonded via any atom in such substituent. Forexample, when the substituent is piperidinyl, morpholinyl, or pyridinyl,unless specified otherwise, said piperidinyl, morpholinyl, or pyridinylgroup may be bonded to the rest of the compound of Formula (I) via anyatom in such piperidinyl, morpholinyl, or pyridinyl group.

Combinations of substituents and/or variables are permissible only ifsuch combinations result in stable compounds. By stable compound orstable structure it is meant herein a compound that is sufficientlyrobust to survive isolation to a useful degree of purity from a reactionmixture, and formulation into an efficacious therapeutic agent.

The term “substituted”, as used herein, means that any one or morehydrogen on the designated atom is replaced with a selection from theindicated group, provided that the designated atom's normal valency isnot exceeded, and that the substitution results in a stable compound.When a substitent is keto (i.e., ═O), then 2 hydrogens on the atom arereplaced.

As used herein, “alkyl” or “alkylene” is intended to include bothbranched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms; for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Examples of alkyl include, butare not limited to, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl,sec-butyl, t-butyl, pentyl, and hexyl.

“Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration, having the specified numberof carbon atoms, and one or more unsaturated carbon-carbon bonds whichmay occur in any stable point along the chain, such as ethenyl,propenyl, 1-butenyl, 2-butenyl and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither a straight or branched configuration, having the specified numberof carbon atoms, and one or more carbon-carbon triple bonds which mayoccur in any stable point along the chain, such as ethynyl, propynyl,1-butynyl, 2-butynyl and the like.

The term “haloalkyl” is intended to include both branched andstraight-chain saturated aliphatic hydrocarbon groups having thespecified number of carbon atoms, substituted independently with 1 ormore halogens (for example —C_(v)F_(w) where v=1 to 3 and w=1 to(2v+1)), such as, but not limited to, —CH₂F, —CHF₂, —CF₃, —CF₂Br,—CH₂CF₃, —CF₂CF₃, —CH(CF₃)₂ and the like.

As used herein, “alkyloxy” or “alkoxy” represents an alkyl group ofindicated number of carbon atoms attached through an oxygen bridge, forexample methoxy, ethoxy, propoxy, i-propoxy, butoxy, i-butoxy, s-butoxyand t-butoxy. The term “aryloxy” is intended to mean phenyl or naphthylattached through an oxygen bridge;

The term “cycloalkyl” is intended to include saturated ring groupshaving the specified number of carbon atoms, including mono-, bi-, orpoly-cyclic ring systems, such as cyclopropyl (c-Pr), cyclobutyl (c-Bu),cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, [3.3.0]bicyclooctyl,[2.2.2]bicyclooctyl, adamantyl and so forth. More specifically,“bicycloalkyl” is intended to include saturated bicyclic ring groupshaving the specified number of carbon atoms, such as[3.3.0]bicyclooctyl, [4.3.0]bicyclononyl, [4.4.0]bicyclodecyl (decalin),[2.2.2]bicyclooctyl, and so forth.

Additionally, the terms “alkylene”, “alkenylene”, “phenylene”, and thelike, refer to alkyl, alkenyl, and phenyl groups, respectively, whichare connected by two bonds to the rest of the structure of Formula I.Such “alkylene”, “alkenylene”, “phenylene”, and the like, mayalternatively and equivalently be denoted herein as “-(alkyl)-”,“-(alkenyl)-” and “-(phenyl)-”, and the like.

“Halo” or “halogen” as used herein refers to fluoro, chloro, bromo andiodo; and “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate and thelike.

As used herein, “aryl” or “aromatic residue” is intended to mean 6 to 10membered monocyclic or bicyclic unsaturated carbon ring, for examplephenyl or naphthyl. As used herein “aryl” is optionally substituted with0-3 groups independently selected from methyl, methoxy, amino, hydroxy,halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, SCH₃, S(O)CH₃, SO₂CH₃,—N(CH₃)₂, C₁-C₄ haloalkyl, methylenedioxydiyl, or ethylenedioxydiyl.

The term “arylalkyl” represents an aryl group attached through an alkylbridge having the specified number of carbon atoms.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3- to 7-membered monocyclic or bicyclic or 7- to14-membered bicyclic or tricyclic or an up to 26-membered polycycliccarbon ring, any of which may be saturated, partially unsaturated, oraromatic. Examples of such carbocyles include, but are not limited to,cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl,indanyl, adamantyl, or tetrahydronaphthyl (tetralin).

As used herein, the term “heterocycle” or “heterocyclic” is intended tomean a stable 5- to 7-membered monocyclic or bicyclic, 7- to 10-memberedbicyclic, or a 10- to 14 membered tricyclic heterocyclic ring which maybe saturated, partially unsaturated, or aromatic, and which consists ofcarbon atoms and from 1 to 4 heteroatoms independently selected from thegroup consisting of N, O and S and wherein the nitrogen and sulfurheteroatoms may optionally be oxidized, and the nitrogen may optionallybe quaternized, and including any bicyclic group in which any of theabove-defined heterocyclic rings is fused to a benzene ring. Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom which results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. Examples of such heterocyclesinclude, but are not limited to, pyridyl (pyridinyl), pyrimidinyl,furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl,tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl,isoxazolinyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl,4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl,tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl,2,3-dihydro-1H-benzo[de]isoquinoline, decahydroquinolinyloctahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl,xanthenyl, phenoxathiinyl, 2H-pyrrolyl, isothiazolyl, isoxazolyl,oxazolyl, pyrazinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl,1H-indazolyl, purinyl, 4H-quinolizinyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole,carbazole, 9-carbolinyl, phenanthridinyl, acridinyl, perimidinyl,phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl,phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl,pyrazolidinyl, pyrazolinyl, piperazinyl, indolinyl, isoindolinyl,quinuclidinyl, morpholinyl, oxazolidinyl, 1,4-benzoxazine,8-oxa-3-azabicyclo[3.2.1]octane, and1,2,3,4-tetrahydro-2,7-naphthyridine. Generally, preferred heterocyclicrings are pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl,triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, isoxazolyl, isoxazolinyl,benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl,3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl. Preferredheterocyclic rings, when R² and R²b can be taken together with thenitrogen atom to which they are attached to form a 5-14 memberedheterocyclic ring system, are morpholine, piperidine, piperazine,pyrrolidine, tetrahydroisoquinoline, thiazolidine, thiomorpholine,1,4-benzoxazine, 8-oxo-3-azabicyclo[3.2.1]octane,2,6-dimethylmorpholine, 2,6-dimethylpiperazine,1,2,3,4-tetrahydro-2,7—Naphthyridine, 1,4-dioxa-8-azaspiro[4.5]decane,azepine, and 2,3-dihydro-1H-benzo[de]isoquinoline. Also included arefused ring and spiro compounds containing, for example, the aboveheterocycles.

As used herein, the term “heteroaryl” refers to aromatic heterocyclicgroups. Such heteroaryl groups are preferably 5-6 membered monocylicgroups or 8-10 membered fused bicyclic groups. Examples of suchheteroaryl groups include, but are not limited to pyridyl (pyridinyl),pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl,imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyridazinyl,benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, orisoquinolinyl.

As used herein, the term “chiral amine” refers to any amine containingcompound that also contains a chiral center. Such compounds include, byway of example and without limitation, either enantiomer ofcinchonidine, ephedrine, 2-phenylglycinol, 2-amino-3-methoxy-l-propanol,quinidine and pseudoephedrine.

As used herein, “carbonyl” means a carbon double bonded to oxygen andadditionally substituted with two groups through single bonds;“carbonyloxy” means a carbon double bonded to oxygen and additionallybonded through a single bonds to two groups, one of which is an oxygen.As used herein, “sulfonyl” is intended to mean a sulfur bonded throughdouble bonds to two oxygens and bonded to two additional groups throughsingle bonds.

As used herein, any carbon range such as “C_(x)-C_(y)” is intended tomean a minimum of “x” carbons and a maximum of “y” carbons representingthe total number of carbons in the substituent to which it modifies, forexample C₁-C₆ alkyl or C₃-C₁₀ cycloalkyl(C₁-C₆ alkyl)- or aryl(C₁-C₆alkyl) or aryl(C₁-C₆ alkyl)carbonyl means an alkyl substituent of one tosix carbons independent of the cycloalkyl, aryl or carbonylrespectively. However, if not specified, for example in “C₂-C₁₀alkylcarbonyloxyalkyloxy” or “C₄-C₁o cycloalkylcarbonyloxyalkyloxy” or“C₇-C₁₁ aryloxycarbonyl-alkyloxy”, the carbon range “C_(x)-C_(y)” isintended to mean the range of total number of carbons in the substituentnot including the “carbonyl”.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound of Formula (I) ismodified by making acid or base salts of the compound of Formula I.Examples of pharmaceutically acceptable salts include, but are notlimited to, mineral or organic acid salts of basic residues such asamines; alkali or organic salts of acidic residues such as carboxylicacids; and the like.

Since prodrugs are known to enhance numerous desirable qualities ofpharmaceuticals (e.g., solubility, bioavailability, manufacturing, etc .. . ) the compounds of the present invention may be manufactured ortherapeutically delivered in prodrug form. Thus, the present inventionis intended to cover prodrugs of the presently claimed compounds,methods of delivering the same, and compositions containing the same.“Prodrugs” are considered to be any covalently bonded carriers whichrelease the active parent drug according to Formula (I) in vivo whensuch prodrug is administered to a mammalian subject. Prodrugs of thecompounds of Formula (I) are prepared by modifying functional groupspresent in the compounds in such a way that the modifications arecleaved, either in routine manipulation or in vivo, to the parentcompounds. Prodrugs include compounds of Formula (I) wherein hydroxyl,amino, sulfhydryl, or carboxyl groups are bonded to any group that, whenadministered to a mammalian subject, cleaves to form a free hydroxyl,amino, sulfhydryl, or carboxyl group, respectively. An example any groupthat, when administered to a mammalian subject, cleaves to form a freeamino, is disclosed in the definition of R², R^(2b), or R³, as “acleavable protecting group.” Examples of prodrugs include, but are notlimited to, acetate, formate and benzoate derivatives of alcohol andamine functional groups in the compounds of Formula I, and the like.Examples of representative amino and carboxyl prodrugs are includedunder the definitions of R², R^(2b), R³, and Y.

The pharmaceutically acceptable salts of the compounds of Formula (I)include the conventional non-toxic salts or the quaternary ammoniumsalts of the compounds of Formula (I) formed, for example, fromnon-toxic inorganic or organic acids. For example, such conventionalnon-toxic salts include those derived from inorganic acids such ashydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric andthe like; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the compounds of Formula (I) which contain a basic oracidic moiety by conventional chemical methods. Generally, the salts areprepared by reacting the free base or acid with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidor base in a suitable solvent or various combinations of solvents.

The pharmaceutically acceptable salts of the acids of Formula (I) withan appropriate amount of a base, such as an alkali or alkaline earthmetal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium,or an organic base such as an amine, e.g., dibenzylethylenediamine,trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or aquaternary ammonium hydroxide such as tetramethylammoinum hydroxide andthe like.

As discussed above, pharmaceutically acceptable salts of the compoundsof the invention can be prepared by reacting the free acid or base formsof these compounds with a stoichiometric amount of the appropriate baseor acid, respectively, in water or in an organic solvent, or in amixture of the two; generally, nonaqueous media like ether, ethylacetate, ethanol, isopropanol, or acetonitrile are preferred. Lists ofsuitable salts are found in Remington's Pharmaceutical Sciences, 17thed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosureof which is hereby incorporated by reference.

The disclosures of all of the references cited herein are herebyincorporated herein by reference in their entirety.

Synthesis

The compounds of the present invention can be prepared in a number ofways well known to one skilled in the art of organic synthesis. Thecompounds of the present invention can be synthesized using the methodsdescribed below, together with synthetic methods known in the art ofsynthetic organic chemistry, or variations thereon as appreciated bythose skilled in the art. Preferred methods include, but are not limitedto, those described below. All references cited herein are herebyincorporated in their entirety herein by reference.

A convenient method for the synthesis of the compounds of this inventionutilizes a dipolar cycloaddition of nitrile oxides with appropriatedipolarophiles to prepare the isoxazoline rings present in compounds ofFormula (I) (for reviews of 1,3-dipolar cycloaddition chemistry, see1,3-Dipolar Cycloaddition Chemistry (Padwa, ed.), Wiley, New York, 1984;Kanemasa and Tsuge, Heterocycles 1990, 30, 719).

Scheme I describes one synthetic sequence to compounds of Formula (Ia)of this invention where n=1. An appropriately substituted oxime, forexample 4-cyanobenzaldoxime, is treated with NCS inN,N-dimethylformamide according to the method of Liu, et al. (J. Org.Chem. 1980, 45, 3916). The resulting hydroximinoyl chloride is thendehydrohalogenated in situ using TEA to give a nitrile oxide, whichundergoes a 1,3-dipolar cycloaddition to a BOC-protected4-allylpiperidine or piperazine derivative to afford the isoxazoline.Alternatively, the oxime may be oxidatively chlorinated,dehydrochlorinated and the resulting nitrile oxide trapped in situ by asuitable alkene under phase transfer conditions according to the methodof Lee (Synthesis 1982, 508). The BOC protecting group on the piperidineor piperazine nitrogen is then removed and the resulting amine alkylatedwith a suitably derivatized alkylating agent, for example, ethylbromoacetate. The benzonitrile is then converted to the correspondingamidine via the imidate, thioimidate or amidoxime under standardconditions known to one skilled in the art. Ester saponification (LiOHor NaOH, THF or MeOH/H₂O) provides the final products.

Various 4-allylpiperidine or 4-allylpiperazine intermediates useful forthe synthesis of compounds of Formula (I) are prepared as outlined inScheme 2. For compounds of Formula (Ia) wherein R⁷ is an oxygen linkedsubstituent, commercially available N-BOC-4-piperidone is treated withallyl magnesium bromide to provide an allylic alcohol. For compounds ofFormula (Ia) wherein R⁷ is hydrogen, piperidine 4-ethanol is firstprotected with di-t-butyl dicarbonate and then oxidized to thecorresponding aldehyde using one of a variety of oxidization proceduresuseful for the conversion of alcohols to aldehydes (i.e., Swern-typeoxidations, chromium based oxidants such as pyridinium chlorochromate,Dess-Martin oxidation, TEMPO/NaOCl, etc.). For compounds of Formula(Ib), commercially available Boc-protected piperazine is alkylated withallyl bromide to give the analogous alkene starting material for the1,3-dipolarcycloaddition. Alternatively as shown in Scheme 2, method d,condensation of N-allyl bis(N,N-2-chloroethyl)amine with a suitablysubstituted alpha or beta amino ester provides additional allylpiperazines useful for the synthesis of compounds of this invention.Compounds with substitution on the piperazine or piperidine ring, can beprepared in an analogous manner from the parent substituted heterocyclesby first protecting with tBOC anhydride followed by introduction of theolefin by one of the methods described above. An example is illustratedin Scheme 2, method e. In this case the starting tetrahydroquinoxalinesare available by reduction of the corresponding quinoxalines or bycyclization of a suitably substituted 1,2-phenylenediamine with1,2-dibromoethane.

Alternately, compounds suitable for conversion to compounds of FormulaIb can be prepared by alkylation of an appropriately monoprotected orderivatized piperazine intermediate with a sulfonate or halide ofFormula 1, as shown in Scheme 3. Compounds of Formula 1 are in turnprepared from the corresponding alcohols which can be obtained fromallyl alcohol by 1,3-dipolar cycloaddition as described above.

Enantioselective synthesis of Compound 1 in Scheme 3 can be achieved bycarrying out the 1,3-dipolar cycloaddition of allyl alcohol to4-cyanobenzaldoximinochloride in the presence of diethyl zinc and D- orL-diisopropyltartrate as described by Ukaji et al. (Chem. Lett. 1993,1847).

Compounds of Formula (Ia) where R⁵R⁶ are not both hydrogen can beprepared as outlined in Scheme 4. BOC-protected nipecotic acid iscondensed with N,O-dimethylhydroxylamine. The resulting Weinreb amide istreated with vinyl magnesium bromide to provide the α,β-unsaturatedketone. Cycloadditon with a nitrile oxide prepared from any of theoximes described above provides the isoxazoline. Various R⁵ substituentscan then be introduced by modification of the ketone function. Forexample, reduction of the carbonyl to the corresponding alcohol andsubsequent alkylation or acylation will provide compounds with R⁵substituents linked through oxygen. Alternately, reductive amination ofthe ketone with various amines will provide amino R⁵ substituents.Wittig olefination optionally followed by reduction of the resultingdouble bond provides additional R⁵/R⁶ substituents. Treatment with aGrignard reagent will give compounds where R⁵ is hydroxy and R⁶ isalkyl. The compound wherein R⁵ and R⁶ are both fluoro can also preparedfrom this intermediate by treatment of the keto compound with DAST. Allof the resulting intermediates can then be converted to the targetcompounds as described above.

Compounds of this invention of Formula (I) wherein one or both of R² andR^(2b) are not hydrogen may be prepared by substitution of anappropriate primary or secondary amine for the ammonium acetate in thesecond step of the Pinner reaction as illustrated in Scheme 5.

Routes to additional aldehydes that can serve as starting materials forthe oxime intermediates useful in the synthesis of the compounds of thisinvention where R¹ is not a phenylamidine are outlined in Scheme 6.

Compounds of this invention where n=2 can be prepared in similar fashionto the corresponding piperazine compounds (n=1) from commericallyavailable homopiperazine as outlined in Scheme 7.

In similar fashion to the methods already described, compounds of theinvention wherein R^(7a) and R^(7b) are taken together to be a ketogroup, are prepared from the commercially available Cbz-protected2-oxopiperazine as shown in Schemes 8a and 8b.

Compounds wherein either R⁷ and R^(7a) or R⁷ and R⁵ are taken togetherto be a double bond are prepared from the 4-hydroxypiperidineintermediate prepared in Scheme 1 above by treatment withmethanesulfonyl chloride. The resulting mesylate eliminates in situ togive a mixture of double bond isomers which are separated by flashchromatography. Each isomer can then be converted to the correspondingtarget compounds as shown in Scheme 9 below.

Compounds of the invention where b is a double bond are prepared asshown in Scheme 10. The starting methyl isoxazole was obtained from basetreatment of the mesylate derived from compound 1. Bromination withN-bromosuccinimde in the presence of a radical initiator provided thebromomethyl derivative which was used to alkylate the commericallyavailable ethyl 2-piperazinoacetate. The resulting product wastransformed into the desired target compounds using methods describedabove.

The compounds of this invention and their preparation can be furtherunderstood by the following procedures and examples, which exemplify butdo not constitute a limit of their invention.

EXAMPLE 1

2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-vlmethyl]-4-hvdroxypiperidin-1-yl]aceticAcid

Part A: N-t-butoxycarbonyl-4-piperidone:

To a solution of 4-piperidone monohydrate hydrochloride (20 g; 0.13 mol)and di-t-butyldicarbonate (43 g; 0.195 mol) in 1,4-dioxane (100 ml) wasadded a solution of sodium hydroxide (13 g; 0.325 mol) in water (150ml). The mixture was stirred at room temperature for 18 h. After removalof the solvent, 400 ml water was added, and the product was extractedinto ethyl acetate (3×200 ml). The extract was washed with brine anddried over anhydrous magnesium sulfate, filtered and concentrated invacuo. Recrystalization of the solid residue from petroleum etherprovided the title compound (19.3 g) as a white solid. An additional 3.5g was obtained by evaporation of the mother liquor and flashchromatograghy (4:1/Hex: ethyl acetate) of the resulting residue (88%).MS(NH₃-CI) m/z 200.3(85). ¹HNMR(CDCl₃) δ: 3.72(t, J=6.2, 4H); 2.44(t,J=6.2, 4H) ppm; 1.49(s, 9H) ppm

Part B: 4-allyl-1-t-butoxycarbonyl-4-hydroxypiperidine:

The compound of Ex. 1., Part A (2.5 g, 12.6 mmol) was dissolved intetrhydrofuran (20 ml) and the resulting solution added dropwise to asolution of allylmagnesium chloride in tetrahydrofuran (1.0 M, 30 ml, 30mmol) at −15° C. to −10° C. After the addition was complete, the mixturewas stirred for 1 h then quenched with saturated ammonium chloridesolution (35 ml) and extracted with ether (3×100 ml). The combinedextracts were washed with brine, dried over anhydrous magnesium sulfate,filtered and concentrated to give the desired product as yellow oil.(2.4g, 80%). MS(NH₃-CI) m/z 242.2 (30, M+H-Boc)+142.3(100, M+H).¹HNMR(CDCl₃) δ 5.87 (m, 1H); 5.22 (m, 3H) 3.81 (brd, 2H): 3.16 (brd,2H); 2.24 (m, 2H); 1.54 (m, 4H); 1.46 (s, 9H) ppm.

Part C:1-t-butoxycarbonyl-4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]-4-hydroxypiperidine:

A solution of triethylamine (1.2 g, 11.95 mmol) in methylene chloride(20 ml) was added dropwise to a solution containing the compound of Ex.1, Part B (2.4 g, 9.96 mmol) in methylene chloride and4-cyanobenzaldehyde oxime (1.8 g, 9.96 mmol) at room temperature over 2h followed by continued stirring at room temperature for a further 3 h.at which time no starting material was detected by TLC. Triethylaminehydrochloride was removed by filtration, and the filtrate wasconcentrated, and extracted with ethyl acetate (3×). The combinedorganic extracts were washed with 5% citric acid (1×), sat. sodiumbicarbonate (1×), brine (1×), and then dried over anhydrous magnesiumsulfate. Filtration and concentration of the filtrate in vacuo wasfollowed by purification using flash chromatography (2:1/Hex: ethylacetate) to give the title compound (1.7 g) as a solid (45%). MS(AP+)(M+H-Boc)⁺ 286.2 (100) ¹HNMR(CDCl₃) δ 7.77(d, J=8.8, 2H); 7.71(d, J=8.8,2H); 5.15(m, 1H); 3.85(brd, 2H); 3.53(m, 1H); 3.25(m, 2H); 3.06(m, 1H);2.33 (s, 1H); 2.05(m, 1H); 1.82(m, 1H); 1.65(m, 3H); 1.46(s, 9H) ppm.

Part D: Ethyl[4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]-4-hydroxypiperidin-1-yl]acetate:

The compound of Ex. 1, Part C (2.5 g, 6.49 mmol) was dissolved in1,4-dioxane (20 ml) and treated with 4M HCl in dioxane (25 ml) solution.The mixture was stirred at room temperature for 4 hr. Removal of thesolvent and trituration with ether (3×) gave, after drying in vacuo, theamine salt (2.1 g, 100%) as white solid which was used without furtherpurification in subsequent transformations.

A portion of this product (0.46 g, 1.43 mmole) was dissolved in DMF (5ml) and potassium carbonate (0.49 g, 3.58 mmol) was added. The mixturewas stirred for 15 min at room temperature followed by addition of Ethylbromoacetate (0.36 g, 2.15 mmol). The reaction was stirred at roomtemperature for 3 h. at which time no starting material remained by TLC.The reaction mixture was diluted with water and extracted with ethylacetate (3×). The combined extracts were washed with water (3×) andbrine (1×), and then dried over anhydrous magnesium sulfate. Filtrationand concentration of the filtrate in vacuo was followed by purificationusing flash chromatography (10:10:1/methylene chloride:ethylacetate:EtOH) to provide the monoalkylated product (0.17 g, 34%)LRMS(ESI) m/z 372.3 (100). ¹HNMR(CDCl₃) δ: 7.7(m, 4H); 5.14(m, 1H);4.21(Q, J=7, 2H); 3.52(m, 1H); 3.24(s, 2H); 3.06(m, 1H); 2.75(m, 2H);2.58(m, 2H); 2.05(m, 1H); 1.84(m, 5H); 1.28(t, J=7, 3H) ppm.

Part E: Ethyl[4-[3-[(4-aminoiminophenyl)isoxazolin-5-yl]methyl]-4-hydroxypiperidin-1-yl]acetate:

The compound of Ex. 1, part D (0.17 g, 0.46 mmol) was dissolved inethanol (5 ml), and hydroxylamine hydrochloride (0.12 g, 1.7 mmol) wasadded followed by triethylamine (0.24 ml, 1.7 mmol). The mixture washeated to reflux for 3 hr. Mixture was cooled to 0° C. and filtered, andthe solid rinsed with cold EtOH, and dried in vacuo at 50° C. for 18 hrto give the amidoxime intermediate (0.134 g, 72%) as a white solid.LRMS(ESI) m/z 405.3 (100). ¹H NMR(DMSO) δ 9.79(s, 1H); 7.73(m, 4H);5.89(s, 2H); 4.87(m, 1H); 4.26(s, 1H): 4.08(Q, J=7, 2H); 3.56(m, 1H);3.16(m, 3H); 1.93(m, 1H); 1.73(m, 1H); 1.66(m, 3H); 1.48(m, 1H); 1.19(t,J=7, 3H) ppm. The solid was suspended in glacial acetic acid (5 ml) andAc2O (0.047 ml, 0.497 mmol) was added. The mixture was stirred for 20min at room temperature followed by addition of 5% Pd/carbon (14 mg).The mixture was stirred under 1 atm H₂ for 4 h. The catalyst was removedby filtration through a pad of Celite, and filtrate concentrated, anddried in vacuo to give the amidine (0.14 g, 100%) as a white solid.LRMS(ESI) m/z 389.3 (100). ¹H NMR(DMSO) δ 7.85(s, 4H); 4.95(m, 1H);4.11(Q, J=7, 2H); 3.60(m, 1H); 3.16(m, 3H); 2.50(m, 2H); 1.91(m, 3H);1.75(m, 1H); 1.58(m, 3H); 1.48(m, 1H); 1.18(t, J=7, 3H) ppm.

Part F:4-][3-[(4-aminoiminophenyl)isoxazolin-5-yl]methyl]-4-hydroxypiperidin-1-yl]aceticacid:

The compound of Ex. 1, part E (0.14 g, 0.332 mmol) was dissolved in THF(5 ml) and treated with a solution of LiOH (19 mg, 0.67 mmol) in water(2 ml). The resulting mixture was stirred at room temperature for 18 hr.Removal of the solvent followed by purification using reversed phaseprep HPLC provided the title compound (88 mg, 46%). LRMS(ESI) m/z 361.2(100). HRMS for C₁₈H₂₅N₄O₄ 361.1875(calcd); 361.1868(obs). ¹H NMR(D₂O) δ7.68(m, 4H); 4.93(m, 1H); 3.73(m, 2H); 3.55(m, 1H); 3.49(m, 2H); 3.12(m,3H); 1.89(m, 6H) ppm

EXAMPLE 22-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-4-carboxymethoxypiperidin-1-yl]aceticAcid

Part A: Ethyl[4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]-(4-ethoxycarbonylmethoxy)piperidin-1-yl]acetate:

Sodium hydride (60% in mineral oil, 0.14 g, 3.59 mmol) was added to asolution of the compound of Ex. 1, part D (0.33 g, 1.026 mmol) inN,N-dimethylformamide (7 ml), and the resulting mixture was stirred for20 min. To this was slowly added ethyl bromoacetate (0.43 g, 2.57 mmol).The mixture was heated at 60° C. in a oil bath for 18 h. After coolingto room temperature, the reaction mixture was diluted with water (100ml) and extracted with ethyl acetate (3×). The combined extracts werewashed with water (3×) and brine (1×) and then dried over anhydrousmagnesium sulfate. Filtration and concentration of the filtrate in vacuowas followed by purification using flash chromatography(10:10:1/methylene chloride:ethyl acetate:EtOH).to give the desiredbisalkylated product (0.36 g, 76%) along with some monoalkylatedproduct. LRMS(ESI) m/z 458.3 (100). ¹H NMR(CDCl₃) δ 7.74(m, 4H); 5.08(M,1H); 4.21(m, 4H); 3.76(m, 1H); 3.53(m, 1H); 2.90(m, 4H); 2.70(m, 4H);2.08(m, 2H); 1.75(m,4H); 1.27(m, 6H) ppm.

Part B:[4-[3-[(4-aminoiminophenyl)isoxazolin-5-yl]methyl]-(4-ethoxycarbonylmethoxy)piperidin-1-yl]aceticAcid:

Substitution of the compound of Ex. 2, Part A in the procedure of Ex. 1,part F provided the benzamidine. Hydrolysis of the diester according tothe procedure of Ex. 1, part G provided the title compound. LRMS(ESI)m/z 419.3 (100). HRMS for C₂DH₂₇N₄O₆ 419.19304(calcd); 419.1941(obs) ¹HNMR(DMSO) 6 9.34(s, 2H); 9.03(s, 2H); 7.83(s, 4H); 4.91(brd, 1H);4.01(brd, 1H); 3.59(m, 2H); 3.40(m, 2H); 3.11(m, 5H); 2.84(brd, 1H);2.66(brd, 1H); 1.88(m, 5H) ppm.

EXAMPLE 32-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-carboxymethoxyoiperidin-1-yl]aceticAcid

The compound of Ex. 2, part A, (0.5 g, 1.094 mmol) was dissolved inethanol (50 ml) and HCl gas was bubbled into the solution for 30 min at0° C. The flask was then tightly stoppered and stirred at roomtemperature for 24 h. Removal of the solvent, trituration with diethylether (3×) and drying in vacuo for 2 h provided the intermediateimidate. LRMS(ESI) m/z 504.3 (100). The imidate was redissoved inethanol (30 ml) and morpholine (0.48 g, 5.47 mmol) was added. Themixture was stirred at room temperature for 18 hr. Removal of thesolvent and drying in vacuo provided the crude amidine. LRMS(ESI) m/z545.5 (100). The amidine was dissolved in 6N HCl (20 ml) and heated toreflux in a 120° C. oil bath for 3 h. The reaction mixture was cooled toroom temperature and concentrated to remove excess HCl followed bypurification using reversed phase prep HPLC. The title compound was thusobtained in 47% overall yield from the nitrile. LRMS(ESI) m/z 489.4(25); (M+Na)+ 511.4 (100) HRMS for C₂₄H₃₃N₄O₇ 489.2349(calcd);489.2346(obs). ¹HNMR(D20) d: 7.71(d,d, J=8.4, 4H); 4.95(m, 1H); 4.61(m,1H); 3.92(m, 1H); 3.79(m, 2H); 3.63(m, 4H); 3.53(m, 1H); 3.36(m, 2H);3.27(m, 4H); 3.06(m, 1H); 2.87(d, J=6.2, 2H); 1.92(m, 4H); 1.82(m, 2H)ppm.

Similarly prepared from the compound of Ex. 2, Part A by substitution ofthe indicated amines in the procedure of Ex. 3 were:

EXAMPLE 42-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]yl]isoxazolin-5-ylmethyl]-4-carboxymethoxypiperidin-1-yl]aceticAcid

(n-butylamine) LRMS(ESI) m/z 475.4 (100). ¹HNMR(D20) δ: 7.65(q, J=8.3,4H); 4.92(m, 1H); 4.62(m, 1H); 3.97(m, 1H); 3.52(m, 1H); 3.30(m, 6H);3.09(m, 1H); 2.88(m, 2H); 1.91(m, 4H); 1.81(m, 2H); 1.57(m, 2H); 1.27(m,2H); 0.75(t, J=7.3, 3H) ppm

EXAMPLE 52-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-carboxymethoxypiperidin-1-yl]aceticAcid

(2,6-dimethylmorpholine) LRMS(ESI) m/z 517.2 (40); (m+2H)/2 259.4 (100).¹HNMR(D₂O) δ: 7.71(d, J=8.8, 2H); 7.49(d, J=8.5, 2H); 4.95(m, 1H);3.99(m, 1H): 3.85(m, 2H); 3.65(m, 1H); 3.55(m, 1H); 3.40(m, 1H); 3.28(m,4H); 3.10(m,2H); 2.89(m, 4H); 1.92(m,4H); 1.82(m, 2H); 1.13(d, J=6.2,3H); 0.90(d, J=6.2, 3H) ppm

EXAMPLE 62-[4-[3-[4-[(N-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-carboxymethoxypiperidin-1-yl]aceticAcid

(N-methylpiperazine) LRMS(ESI) m/z 502.4 (100). ¹HNMR(D₂O) δ: 7.73(d,J=8.5, 2H); 7.52(d, J=8.4, 2H); 4.95(m, 1H); 4.21(m, 1H); 3.99(m, 1H);3.82(m, 1H); 3.63(m, 4H); 3.45(m, 2H); 3.30(m, 5H); 3.05(m, 2H); 2.91(d,J=6.2, 2H); 2.83(s, 3H); 1.92(m, 4H); 1.82(m, 2H) ppm

EXAMPLE 72-[4-[3-[4-[(piperidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-carboxymethoxypiperidin-1-yl]aceticAcid

(piperidine) LRMS(ESI) m/z 487.3 (80); (m+Na)⁺ 509.3 (100) ¹HNMR(D₂O) δ:7.69(d, J=8.4, 2H); 7.48(d, J=8.8, 2H); 4.95(m, 1H); 4.0(m, 1H); 3.51(m,3H); 3.26(m, 6H); 3.15(m, 1H); 2.92(d, J=5.8, 2H); 1.91(m, 4H); 1.80(m,2H); 1.65(m, 2H); 1.55(m, 2H); 1.45(m, 2H) ppm

EXAMPLE 82-[4-[3-[4-[(N-phenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-carboxymethoxypiperidin-1-yl]aceticAcid

(N-phenylpiperazine) LRMS(ESI) m/z 564.4 (30); (m+2H)/2 282.9 (100).¹HNMR(D₂O) δ: 7.73(d, J=8.4, 2H); 7.54(d, J=8.6, 2H); 7.28(m, 2H);7.10(m, 3H); 4.95(m, 1H); 4.00(m, 1H); 3.87(m, 2H); 3.60(m, 3H); 3.46(m,2H); 3.27(m, 6H); 3.13(m, 1H); 2.92(d, J=5.9, 2H); 1.92(m, 4H): 1.83(m,2H) ppm

EXAMPLE 92-[4-[3-[4-[(N-thiomorpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-carboxymethoxypiperidin-1-yl]aceticAcid

(thiomorpholine) LRMS(ESI) m/z 505.2 (20); (m+2H)/2 253.3 (100). HRMSfor C₂₄H₃₃N₄O₆S₁ 505.2121 (calcd); 505.2139 (obs). ¹HNMR(D₂O) δ: 7.71(d,J=8.4, 2H); 7.49(d, J=8.4, 2H) 4.95(m, 1H); 3.99(m, 1H); 3.87(m, 2H);3.58(m, 3H): 3.28(m, 4H); 3.12(m, 1H); 2.91(d, J=5.9, 2H); 2.78(m, 2H);2.56(m, 2H); 1.92(m, 4H); 1.82(m, 2H) ppm.

EXAMPLE 10

2-[4-[3-[4-[(cis-2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5(S)-ylmethyl]-4-carboxymethoxypiperidin-1-yl]-aceticAcid

The compound of Ex. 2, Part A was resolved by chiral HPLC and thedextrorotary isomer was converted into the title compound using themethod of Ex. 3 and cis-2,6-dimethylmorpholine in the second step of thePinner reaction. LRMS(ESI) m/z 517.2 (40); (m+2H)/2 259.4 (100)¹HNMR(D₂O) δ: 7.71(d, J=8.8, 2H); 7.49(d, J=8.5, 2H); 4.95(m, 1H);3.99(m, 1H): 3.85(m, 2H); 3.65(m, 1H); 3.55(m, 1H); 3.40(m, 1H); 3.28(m,4H); 3.10(m,2H); 2.89(m, 4H); 1.92(m,4H); 1.82(m, 2H); 1.13(d, J=6.2,3H); 0.90(d, J=6.2, 3H) ppm.

EXAMPLE 112-[4-[3-[4-[(tetrahydroisoquinolino)iminomethylphenyl]-isoxazolin-5(S)-yl]methyl]-4-carboxymethoxypiperidin-1-yl]-aceticAcid

LRMS(ESI+) m/z 535.4 (10); (m+2H)/2 268.4 (100) HRMS for C₂₉H₃₅N₄O₆535.2556 (calcd); 535.2580 (obs). ¹HNMR(D₂O) δ: (mixture of rotamers)7.73(m, 2H); 7.51(m, 2H); 7.17(m, 2H); 7.10-6.80 (m, 2H,); 4.95(m, 1H);4.65(m, 3H); 4.41(s, 1H); 3.95(m, 1H); 3.75(m, 1H); 3.55(m, 2H); 3.30(m,3H); 3.10 (m, 2H); 2.90(m, 2H); 2.80(m, 1H); 1.95(m, 4H); 1.859 m, 2H)ppm

EXAMPLE 122-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

Part A: 4-cyanobenzaldoxime:

4-Cyanobenzaldehyde (20 g, 0.15 mol) was dissolved in a 1:1 mixture ofEtOH/pyridine (250 ml) and treated with hydroxylamine hydrochloride(11.7 g, 0.17 mol) portionwise under a nitrogen atmosphere. The reactionwas stirred at room temperature for 16 h before concentrating thesolvent half volume and precipitating the desired product by theaddition of ice water. The white precipitate was filtered, washed withwater and recrystallized from EtOH/H₂O to give 17.3 g (0.118 mol, 77%)of the desired oxime. ¹H-NMR (CDCl₃) 8.14(1H, s), 7.68(4H, s), 7.61 (lH,s).

Part B: 4-cyanobenzaldoximinochloride

The oxime of Ex.7, Part A (43.1 g, 0.29 mol) was dissolved in anhydrousN,N-dimethylformamide under N₂ and N-chlorosuccimide (46.4 g, 0.35 mol)was added portionwise at room temperature After stirring at roomtemperaturefor 16 h, the reaction was poured into 1 L of ice water andthe precipitate was collected by filtration, washed with water and driedovernight in a vacuum oven at 45° C. to give the desired product (48.5g, 92%) as a white solid. 1H-NMR(CDCl₃) 6 8.17(1H, s), 8.00(2H, ),7.73(2H, ).

Part C: 1-t-butoxycarbonyl-4-allylpiperazine:

t-Butyl 1-piperazinecarboxylate (5.0 g, 27 mmol) was dissolved inanhydrous N, N-dimethylformamide (40 ml) under a nitrogen atmosphere. Tothis solution was added potassium carbonate (7.46 g, 56 mmol) and themixture was allowed to stir at room temperature for 20 min. to themixture was added allyl bromide (2.57 ml, 30 mmol), and the whole wasstirred for an additional 3 h. The reaction was diluted with ethylacetate and washed with saturated sodium bicarbonate solution, andbrine. The organic layer was separated, dried over anhydrous sodiumsulfate, filtered and the filtrate evaporated under reduced pressure togive the desired product (4.76 g, 78%) as a clear oil. ¹H-NMR(CDCl₃)5.94-5.80(1H, m), 5.18-5.15(2H, m), 3.44(4H, t, J=5.1 Hz), 3.00(2H, dt,J=6.6, 1.1 Hz), 2.39(4H, t, J=5.1 Hz), 1.46(9H,s).

Part D:1-t-butoxycarbonyl-4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]piperazine:

To a solution of the compound of Ex. 7, part B (3.79 g, 2lmmol) and thecompound of Ex. 7, part C (4.76 g, 21 mmol) in methylene chloride (150ml) was added a solution of triethylamine (3.5 ml, 25.2 mmol) inmethylene chloride (50 ml) dropwise over 2-3 h at room temperature underN₂. After stirring for 18 h, the solvent was removed in vacuo, and theresidue was taken up in ethyl acetate and washed with saturated sodiumbicarbonate solution and brine. The organic layer was dried overanhydrous sodium sulfate, filtered and the filtrate was evaporated. Theresulting oil was purified by flash chromatography (Biotage Flash 40silica column, 3:1 hexane:ethyl acetate) to give the desired product(5.01 g, 70%). ¹H-NMR(CDCl₃) 7.74 (4H, J=24, 8.8 Hz), 5.05-4.93(1H, m),3.35-3.46 (4H, m) 3.21 (1 h, dd, J=17, 8.4 Hz), 2.70-2.64 (2H, m),2.54-1.61(5H, m), 1.46(9H, s); MS(ES+) 315.2 [ (M-tBu)⁺], 371.3[(M+H)⁺].

Part E: Ethyl2-[4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]piperazin-1-yl]acetate

The compound of Ex. 7, Part D (5 g, 0.016 mol) was dissolved in neat TFA(10 ml) under N₂. After stirring at room temperaturefor 1.0 h, themixture was concentrated in vacuo to remove trifluoroacetic acid and theresulting crude yellow oil was dissolved in anhydrous N,N-dimethylformamide and treated with K₂CO₃ (6.2 g, 45 mmol) followed byslow addition of ethyl bromoacetate (1.83 ml, 15 mmol). After 16 h, thereaction was diluted with ethyl acetate and washed with H₂O followed bysaturated sodium bicarbonate solution and brine. The organic layer wasdried over anhydrous sodium sulfate, filtered and evaporated underreduced pressure to give the desired product (3.25 g, 9.4 mmol, 63%) asan off white solid. ¹H-NMR(CD₃OD) 7.77 (4H, dd, J=20, 8.8 Hz), 5.02-4.92(1H, m), 4.15 (2H, q, J=7 Hz), 3.50 (1H, dd, J=17, 10.6 Hz), 3.29-3.14(4H, m), 3.21 (3H, s), 2.67-2.64 (10H, m), 1.24 (3H, t, J=7 Hz) ppm.MS(ES+) 271.2 [(M+H)⁺].

Part F:2-[4-[3-[[4-(morpholinoiminomethyl)phenyyl]isoxazolin-5-yl]methyl]piperazin-1-yl]aceticacid:

The compound of Ex. 7, Part E (3.35 g, 9.4 mmol) was dissolved inethanol (40 ml) and HCl(g) was bubbled in for 30 min at 0° C. Thereaction became gelatinous, but upon further addition of HCl (g), turnedclear. The reaction was stoppered and allowed to slowly come to roomtemperature and stand 16 h at which point, a precipitate had formed. Themixture was then purged with a stream of nitrogen to remove excess HCland the remaining solvent evaporated in vacuo . The resulting residuewas triturated with ether to give the imidate intermediate (2.56 g, 68%)as a white solid. A portion of the imidate intermediate (0.850 g, 2.11mmol) was suspended in anhydrous EtOH and treated with morpholine (0.952mL, 10.5 mmol) at room temperature under N₂ for 16 h. The solvent wasthen removed under reduced pressure and the resulting oily residuepurified by preparatory HPLC (C18/80% CH₃CN:20% H₂O:0.05% TFA) to givethe amidine derivative (49 mg) which was then hydrolyzed in refluxing6.0N HCl for 1.0-1.5 h and again purified by preparatory HPLC to givethe title compound. ¹H-NMR(CD₃OD) 7.83(4H, dd, J=72, 8.4 Hz),5.46-5.41(1H, m), 4.35(2H, s), 3.98-3.85(10H, m), 3.83-3.73(3H, m),3.71-3.69(3H, m), 3.48-3.33(3H, m) ppm; MS(ES+) 416.1 [(M+H)⁺]; Calc'dfor C₂₁H₂₉N₅O₄·3HCl: C,48.06; H,6.15; N,13.34. Found C,48.08; H,6.24;N,13.29.

Similarly prepared from the compound of Ex. 7, Part E using theprocedure of Ex 7, Part F and the indicated amines were:

EXAMPLE 132-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperazin-1-ylacetic Acid

(n-butyl amine) ¹H-NMR(CD₃OD) 7.86(4H, dd, J₁=27.9 Hz, J₂=8.8 Hz),5.53-5.38(1H,m), 4.36(2H, s), 4.00-3.85(7H,bm), 3.81-3.72 (1H, m),3.72-3.70(2H, m), 1.74(2H, m), 1.47(2H, m), 1.00(3H, t, J=7.3); MS(ES+)402.3 [(M+H)⁺], C₂₁H₃₄N₅O₃Cl₃ calc'd for C, 49.37; H, 6.71; N, 13.71;found C, 49.66; H, 6.64; N, 13.52.

EXAMPLE 142-[4-[3-[4-(aminoiminomethyl)phenyyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(ammonium acetate) ¹H-NMR(CD₃QD) δ 7.90(4H, dd, J₁=13.9, 8.4 Hz),5.45-5.33(1H, m), 4.26(2H, s), 3.82-3.73(9H, bm) 3.64-3.61 (2H, m),3.31-3.43 (1H, m) ppm. MS(ES+) 346.3 [(M+H)⁺]; C₁₇H₂₇N₅O₃.3HCl.3H₂O: C,40.13; H, 6.34; N, 13.76. Found: C, 39.98; H, 6.37; N, 13.46.

EXAMPLE 152-[4-[3-[4-[(N-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(N-methylpiperazine) ¹H-NMR(CD₃OD) δ 7.74 (4H, dd, J=74.9, 8.0 Hz)5.20-5.16 (1H, m), 4.09 (2H, bs), 3.73-3.59 (sH, m), 3.55 (2H, s), 3.30(2H, bs), 3.25-3.16 (14H, m) 2.81 (3H, s) ppm. MS(ES+) 429.3 (M+H)⁺.Calc'd for C₂₂H₃₂N₆₃O₃.3TFA.0.5H₂O: C, 40.32; H, 4.17; N, 9.40; F,25.51. Found: C, 40.30; H, 3.92; N, 9.23; F, 25.84.

EXAMPLE 162-[4-[3-[4-[(cis-2,6-dimethylmorpholino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]piperazin-1-ylacetic Acid

(cis-2,6-dimethylmorpholine) ¹H-NMR(CD₃OD) δ 7.79 (4H, dd, J=77.9, 8.4Hz) 5.25-5.11 (1H, m), 4.10-4.08 (1H, m), 3.90-3.78 (1H, m), 3.75-3.60(4H, m), 3.45-3.12 (12H, m), 2.93-3.09 (2H, m), 1.16 (3H, d), J=6.3 Hz)1.04 (3H, d, J=6.2 Hz) pm. MS(ES+) 444.3 (M+H)⁺. Calc'd forC₂₃H₃₃N₅O₄.3TFA: C, 44.34; H, 4.63; N, 8.91; F, 21.74. Found: C, 44.49;H, 4.52; , 8.85; F, 21.83.

EXAMPLE 172-[4-[3-[4-[8-(1,4-dioxa-8-azaspiro[4.5]decyl)]iminomethyl)-phenyl]isoxazolin-5-ylmethyl]-piperazin-1-yl]aceticAcid

(1,4-dioxa-8-azaspiro[4.5]decane) ¹H-NMR (CD₃CN) δ 8.44(1H, bs);8.19(1H, bs); 7.71(4H, dd, J=70.9, 8.5); 5.19-5.16(1H, m); 3.94(4H, m);3.80(2H, m); 3.63(4H,s); 3.53-3.15(14H, m); 1.73(2H,bs) ppm; HRMS calc'dfor C₂₄H₃₄N₅O₅ 472.2560, found: 472.2573; Anal. Calc'd forC₂₄H₃₃N₅O₅.2.7TFA: C,45.13; H, 4.59; N, 8.92; F, 19.96. Found: C, 45.32;H,4.64; N, 8.85; F, 20.38.

EXAMPLE 182-[4-[3-[4-(4-phenylpiperazinoiminomethyl)phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(N-phenylpiperazine) 1H-NMR(CD₃CN) δ 7.75(4H, dd, J=75.9, 8.4); 7.74(2H,d, J=7.4); 7.28(2H, q, J=7.3); 6.98-6.87(3H, m); 5.25-5.20(1H, m);3.84(2H, m); 3.76(2H, s); 3.71-3.17(18H, m); HRMS calc'd for C₂₇H₃₅N₆O₃491.2770, found: 491.2764; C₂₇H₃₁N₆O₃.2.3 TFA calc'd for C, 50.82; H,5.20; N, 11.41; found: C, 50.54; H,4.92; N, 11.00.

EXAMPLE 192-[4-[3-[4-[(cis-3,5-dimethylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(cis-3,5-dimethylpiperazine) ¹H-NMR(CD₃CN) δ 8.83(1H, bs); 8.31(1H, bs);7.79(4H, dd, J=68.7, 8.0); 5.20-5.17(1H, m); 4.27(1H, d J=9.6); 3.64(7H,bs), 3.58-3.12(13H, bs); 1.42(3H, s); 1.18(3H, d, J=5.9); HRMS calc'dfor C₂₃H₃₅N₆O₃ 443.2770; found: 443.2771; Anal. calc'd forC₂₃H₃₄N₆O₃.4.3TFA C, 41.43; H, 4.26; N, 9.35; F, 25.37. Found: C, 40.69;H, 4.14; N, 9.01; F, 26.27.

EXAMPLE 202-[4-[3-[4-[[4-(2-fluorophenyl)piperazino]iminomethyl]-phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(N-(2-fluorophenyl)piperazine) ¹H-NMR(CD₃OD) δ 7.82(4H, dd, J=67.8,8.4); 7.13-6.98(4H, m); 5.23-5.13(1H, m); 3.96(2H, t, J=4.4); 3.76(2H,s); 3.70-3.62(2H, m); 3.36-3.16(16H, m); HRMS calc'd for C₂₇H₃₄N₆O₃F509.2676; found: 509.2675.

EXAMPLE 212-[4-[3-[4-[[4-(2-methylphenyl)piperazino]iminomethyl]-phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(N-(2-methylphenyl)piperazine) ¹H-NMR(CD₃OD) δ 7.83(4H, dd, J=66.3,8.4); 7.20-6.97(4H, m); 5.13-5.08(1H, m); 3.95(2H, t, J=0.25);3.72-3.60(SH, m); 3.28-3.11(13H,m); 2.95(2H, t, J=0.25); 2.32(3H, s);HRMS calc'd for C₂₈H₃₇N₆O₃ 505.2927; found: 505.3353.

EXAMPLE 222-[4-[3-[4-(morpholinoiminomethyl)phenyl]isoxazolin-5(S)-ylmethyl]piperazin-1-yl]aceticAcid

(morpholine) ¹H-NMR(CD₃OD) δ 7.82(4H, dd, J=75.1, 8.4); 5.30-5.40(1H,m); 4.20 (2H, s); 3.90 (2H, t, J=4.0); 3.81-3.73(13H, m); 3.58-3.55 (2H,m); 3.45 (2H, t, J=5.1); 3.40-3.32(1H, m); HRMS calc'd for C₂₁H₃₀N₅O₄416.2298; found: 416.2313. [α]_(D)+80.30 (c, 0. MeOH)

EXAMPLE 232-[4-[3-[4-(morpholinoiminomethyl)phenyl]isoxazolin-5(R)-ylmethyl]piperazin-1-yl]aceticAcid

(morpholine) 1xH-NMR(CD₃OD) δ 7.82(4H, dd, J=74.7, 8.1); 5.43-5.39(1H,m); 4.29(2H, s); 3.92-3.64(17H, m); 3.46(2H, t, J=4.7); 3.38(1H, dd,J=17.4, 7.0); HRMS calc'd for C₂₁H₃₀N₅O₄ 416.2298; found: 416.2306.[α]_(D)−88.40 (c, 0. MeOH).

EXAMPLE 242-[4-[3-[4-[2-(4-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethylpiperazin-1-yl]acetic Acid

(2-(4-pyridyl)ethylamine) ¹H NMR (MeOH-d4) d 8.80 (d, J=6.2 z, 2H), 8.03(d, J=6.2 Hz, 2H), 7.9 (d, J=8.8 Hz, 2H), 7.79 (d, J=8.8 Hz, 2H), 5.2(m, 1H), 3.88 (t, 2H), 3.74 (s, 2H), 3.2 (m, 1H), 3.40 (t, 2H),3.29-3.22 (11H); MS (ESI) m/z 451.4 (100%, M+H⁺); HRMS (FAB) found(M+H⁺) 451.2449;

EXAMPLE 252-[4-[3-[4-[(phenethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(phenethyl amine) ¹H NMR (MeOH-d4) d 7.86 (d, J=8.4 Hz, 2H), 7.66 (d,J=8.4 Hz, 2H), 7.34-7.24 (5H), 5.2 (m, 1H), 5.03 (s, 2H), 3.79 (s, 2H),3.74 (t, 2H), 3.66 (m, 1H), 3.32-3.21 (11H), 3.04 (t,2H); MS (ESI) m/z450.3 (100%, M+H⁺); HRMS (FAB) found. (M+H⁺) 450.2512;

EXAMPLE 262-[4-[3-[4-[(isobutylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(isobutylamine) ¹H NMR (MeOH-d₄) d 7.9 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.3Hz, 2H), 5.2 (m, 1H), 3.78 (s, 2H), 3.6 (m, 20 1H), 3.2-3.95 (m, 13H),2.08 (m, 1H), 1.04 (d, J=6.6 Hz, 6H); MS (ESI) m/z 402.3 (100%, M+H⁺);HRMS (FAB) found (M+H⁺) 402.2496; Anal. calcd. for C₂₁H₃₁N₅O₃.2.7TFA: C,44.59; H, 4.77; N, 9.83; F, 21.83. Found: C, 44.75; H, 4.83; N, 9.75; F,22.19.

EXAMPLE 27 2-[4-[3-[4-[(cyclopropylmethylamino)iminomethyl]phenyl-isoxazolin-5-ylmethyl]piperazin-1-yl]acetic Acid

(cyclopropylamine) ¹H NMR (MeOH-d₄) d 7.9 (d, J=8.8 Hz, 2H), 7.79 (d,J=8.4 Hz, 2H), 5.2 (m, 1H), 3.78 (s, 1H), 3.2-3.95 (m, 13H), 1.2 (m,1H), 0.65 (m, 2H), 0.36 (m, 2H); MS (ESI) m/z 400.3 (M+H⁺); HRMS (FAB)calcd. (M+H⁺), found; Anal. calcd for C₂₁H₂₉N₅O₃.3TFA: C, 43.73; H,4.359; N, 9.44. Found: C, 43.62; H, 4.16; N, 9.38.

EXAMPLE 282-[4-[3-[4-[(Propargylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(propargylamine) ¹H NMR (MeOH-d₄) δ 7.9 (d, J=8.4 Hz, 2H), 7.79 (d,J=8.4 Hz, 2H), 5.2 (m, 1H), 4.3 (m, 2H), 3.78 (s, 2H)3, 3.66 (dd,J=17.2, 1 7.2 Hz, )H), 3.2-3.95 (m, 12H); MS (ESI) m/z 384.3 (100%,M+H⁺); HRMS (FAB) calcd. (M+H⁺) found ; Anal. calcd. forC₂₀H₂₅N₅O₃.3TFA: C, 43.04; H, 3.89; N, 9.65. Found: C, 43.00; H, 3.76;N, 9.51. 1.0

EXAMPLE 292-[4-[3-[4-[(N,N-diethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(diethylamine) ¹H NMR (MeOH-d₄) δ 7.91 (d, J=8.4 Hz, 2H), 7.63 (d, J=8.5Hz, 2H), 5.2 (m, 1H) 3.75 (s, 2H), 3.65 (m, 3H), 3.19-3.4 (d , 13H),1.36 (t, J27.3 Hz, 3H), 1.167 (t, J=7.0 Hz, 3H); MS (ESI) m/z 402.3(100%, M+H+);

EXAMPLE 302-[4-[3-[4-[(N-methyl-N-benzylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(N-methyl-N-benzylamine) ¹H NMR (MeOH-d₄) d 7.91 (m, 2H), 7.70 (m, 2H),7.38 (m, 3H), 7.18 (d, J s6.2 Hz, 2H), 5.2 (m, 1H), 4.58 (s, 2H), 3.80(s, 2H), 3.67 (dd, J=17.2, 17.2 Hz, ), 3.22-3.4 (m, 11H), 3.21 (s, 3H);MS (ESI) m/z 450.3 (100%, M+H⁺); Anal.calcd. for C₂₅H₃₁N₅O₃.3TIFA: C,47.04;H, 4.339; N, 8.857. Found: C, 47.33; H, 4.17; N, 8.87.

EXAMPLE 312-[4-[3-[4-[(N-methyl-N-bhenethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]aceticAcid

N-methyl-N-phenethylamine) ¹H NMR (MeOH-d₄) d 7.6-7.9 (2H), 6.9-7.5(7H), 5.2 (m, 1H), 3.85 (s, 2H), 3.60 (m, 3H), 3.2-3.5 (m, 13H), 3.35(s, 3H); MS (ESI) m/z 464.3 (100%, M+H⁺);

EXAMPLE 322-[4-[3-[4-1(4-pyridylmethylamino)iminomethyyl]phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(4-pyridylmethylamine) ¹H NMR (MeOH-d₄) δ 8.82 (d, J=6.6 Hz, 2H),7.96-7.92 (6H), 5.2 (m, 1H), 5.03 (s, 2H), 3.72 (s, 2H), 3.66 (m, 1H),3.32-3.18 (11H); MS (ESI) m/z 437.3 (100%, M+H⁺); HRMS (FAB) found.(M+H⁺) 437.2295;

EXAMPLE 332-[4-[3-[4-[(2-(2-pyridyl)ethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(2-(2-pyridylethyl)amine) ¹H NMR (MeOH-d₄) δ 8.79 (bd, 1H), 8.53 (m,1H), 8.04-7.78 (6H), 5.2 (m, 1H), 3.96 (t,2H), 3.8 (s, 2H), 3.66 (m,1H), 3.51 (t, 2H), 3.40-3.26 (11H); MS (ESI) m/z 451.4 (100%, M+H⁺);

EXAMPLE 342-[4-[3-[4-[(1—Naphthylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(1—Naphthylmethylamine) ¹H NMR (MeOH-d₄) δ 8.02-7.94 (3H), 7.88 (d,J=8.4 Hz, 2H), 7.68 (d, J=8.4 Hz, 2H), 7.64-7.52 (4H), 5.17 (m, 1H),5.14 (s, 2H), 3.78 (s, 2H), 3.6 (m, 1H), 3.27-3.14 (11H); MS (ESI) m/z486.3 (100%, M+H⁺); HRMS (FAB) found (M+H⁺) 486.2506;

EXAMPLE 352-[4-[3-[4-1(2-pyridylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(2-pyridylmethylamine) ¹H NMR (MeOH-d₄) δ 8.62 (bd, 1H), 8.00-7.86 (5H),7.58 (d, 1H), 7.49 (m, 1H), 5.2 (m, 1H), 4.85 (s, 2H), 3.76 (s, 2H),3.66 (m, 1H), 3.30-3.23 (11H); MS (ESI) m/z 437.3 (100%, M+H⁺); HRMS(FAB) found. (M+H⁺) 437.2298;

EXAMPLE 362-[4-[3-[4-[(N-ethyl-N-methylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]piperazin-1-yl]aceticAcid

(N-ethyl-N-methylamine) ¹H NMR (MeOH-d₄) δ 7.9 (d, J=7.7 Hz, 2H), 7.63(d, J=8.5 Hz, 2H), 5.19 (m, 1H), 3.78 (s, 2H), 3.66 (dd, J=10.7, 10.3Hz, 1H), 3.2-3.4 (m, 12H), 3.28 (s, 3H), 1.1-1.4 (3H); MS (ESI) m/z388.3 (100%, M+H⁺);

EXAMPLE 372-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-4-benzyloxypiperidin-1-yl]aceticAcid

Part A.1-t-butoxycarbonyl-4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]-4-benzyloxypiperidine:

The compound of Ex. 1, Part C (0.5 g, 1.299 mmol) was dissolved in DMF(5 ML) was cooled in ice bath, then sodium hydride (60% in mineral oil,0.12 g, 3.9 mmol was added. The mixture was stirred for 10 min andbenzyl bromide was added slowly. The rxn was stirred at room temperaturefor 3 h, then diluted with water (100 ml) and extracted with ethylacetate (3×). The organic layer was washed with water (3×), brine (2×),dried over anhydrous magnesium sulfate. Filtration and concentration ofthe filtrate in vacuo was followed by purification using flashchromatography (4:1/Hexane:ethyl acetate) to give the desired product(0.5 g, 83%). LRMS(NH₄-CI) 376.1 (M+H-Boc)⁺(100); 476.1 (M+H)⁺ (12);¹HNMR(CDCl₃) δ: 7.68(s, 5H); 7.37(m, 4H); 4.95(d, 1H): 4.48(m, 2H):3.84(d, 2H): 3.40(m, 1H); 3.20(d, 2H); 2.99(m, 1H); 2.20(d, 1H); 2.04(m,3H): 1.65(m, 1H); 1.46(s, 9H) ppm

Part B. Ethyl[4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]-4-benzyloxypiperidin-1-yl]acetate:

Following the procedures of Ex. 1, Part D and E, the compound of Ex. 37,Part A was deprotected and alkylated with ethyl bromoacetate to give thedesired intermediate. LRMS(ESI) m/z 462.2 (100); ¹HNMR(CDCl₃) δ: 7.67(s,5H); 7.37(m, 4H); 4.98(m, 1H); 4.52(d,d, J=11, 2H); 4.20(q, J=7.3, 2H);3.36(m, 1H); 3.23(s, 2H); 2.99(m, 1H); 2.76(m, 2H): 2.57(m, 2H); 2.23(m,1H); 2.07(m, 1H); 1.95(m, 1H): 1.81(m, 3H); 1.27(t, J=7, 3H) ppm.

Part C.4-[3-[(4-aminoiminophenyl)isoxazolin-5-yl]methyl]-4-benzyloxypiperidin-1-yl]aceticAcid:

Using the procedures from Ex. 1, Part F and G the compound of Ex. 37,Part B was converted into the title compound. LRMS(ESI) m/z 451.3 (100);HRMS for C₂₅H₃₁N₄O₄ 451.2345(calcd); 451.2344(obs) ¹HNMR(CD₃OD) δ:7.88(m, 4H): 7.43(m, 5H); 5.00(m, 1H); 4.54(q, J=ll, 2H); 4.02(s, 2H);3.52(m, 3H); 3.15(m, 3H): 2.32(m, 4H); 2.05(m, 3H) ppm.

EXAMPLE 382-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticAcid

Part A. 2-(1-BOC-piperidin-4-yl)ethanol:

To a mixture of 4-piperidineethanol and di-t-butyl dicarbonate inDioxane (15 ml) was added 1N NaOH (30 ml).The reaction was stirred atroom temperature for 18 hr. Solvent was evaporated in vacuo and water(100 ml) was added, followed by extraction with ethyl acetate (3×). Thecombined organic layers were washed with brine and dried over anhydrousmagnesium sulfate. Filtration and concentration of the filtrate in vacuoprovided the product (3.62 g). LRMS(ESI) (M+Na)⁺252.2 (100);¹HNMR(CDCl₃) d: 4.05(brd, 2H); 3.74(m, 2H); 2.69(m, 2H); 1.65(m, 2H);1.55(m, 3H); 1.45(s, 9H); 1.26(m, 1H); 0.60(m, 2H) ppm.

Part B: 2-(1-BOC-piperidin-4-yl)acetaldehyde:

To a cold (0° C.) solution of DMSO:methylene chloride (1:4, 25 ml)contaning the compound of Ex. 38, Part A (3.6 g, 15.72 mmol), was addedtriethylamine (7.9 g, 78.6 mmol) followed by pyridine-sulfur trioxidecomplex (5 g, 31.44 mmol). The reaction mixture was stirred at 0° C. for2 hr, then warmed up to room temperature and stirred overnight. Quenchedwith water (100 ml), separated the layers and concentrated the aqueouslayer. Recombined and extracted with ethyl acetate (3×), washed theorganic layer with water (3×), brine (1×), dried over anhydrousmagnesium sulfate. Filtration and concentration of the filtrate in vacuowas followed by purification using flash chromatography(9:1/Hexanes:ethyl acetate) to give the aldehyde (2.6 g, 74%).LRMS(NH₄-CI) (M+H-Boc)⁺128.3 (100); m/z 228.3(20); ¹HNMR(CDCl₃) δ:9.8(s, 1H); 4.10(brd, 2H); 2.74(m, 2H); 2.39(m, 2H); 2.05(m, 1H);1.66(m, 2H); 1.45(s, 9H); 1.19(m, 2H) ppm.

Part C. 1-BOC-4-allylpiperazine:

the compound of Ex. 38, Part B was converted to the olefin usingconditions for Wittig olefination as described in Synthesis, 1975, 784.The desired allylpiperidine (2.2 g) was obtained in 88% yield afterpurification using flash chromatography (9:1/Hexanes:ethyl acetate).LRMS(H₂O/GS/MS) (M+H-tBu)⁺170 (100); (M+H-Boc)⁺126 (20). ¹HNMR(CDCl₃) δ:5.73(m, 1H); 5.03(m, 1H); 4.98(s, 1H); 4.05(m, 2H); 2.65(m, 2H); 2.00(t,J=7, 2H); 1.65(m, 2H); 1.45(s, 9H); 1.14(M, 2H) ppm.

Part D.1-t-butoxycarbonyl-4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]piperidine:

The cyclization procedure of Ex. 1, Part C was used to convert thecompound of Ex. 38, Part C to the isoxazoline. LRMS(NH₄-CI)(M+H-Boc)⁺270.2 (100); (M+H)⁺370.1 (18). ¹HNMR(CDCl₃) δ: 7.77(m, 4H);4.90(m, 1H); 4.11(brd, 2H); 3.44(m, 1H); 2.94(m, 1H); 2.72(m, 2H);1.83(m, 2H); 1.77(m, 2H); 1.52(m, 1H); 1.45(s, 9H); 1.17(m, 2H) ppm.

Part E. Ethyl[4-[3-[(4-cyanophenyl)isoxazolin-5-yl]methyl]piperidin-1-yl]acetate:

The compound of Ex. 38, Part D was deprotected and alkylated with ethylbromoacetate using the procedures described above in Ex. 1, Part D andE. LRMS(ESI) m/z 356.3 (100); ¹HNMR(CDCl₃) δ: 7.74(d, J=8.4, 2H);7.70(d, J=8.4, 2H); 4.92(m, 1H); 4.20(m, 2H): 3.46(m, 1H); 3.20(s, 2H);2.94(m, 3H); 2.20(m, 2H); 1.80(m, 2H): 1.70(m, 1H): 1.50(m, 4H): 1.27(t,J=7.9, 3 h) ppm.

Part F.4-[[3-[(4-aminoiminophenyl)isoxazolin-5-yl]methyl]piperidin-1-yl]aceticAcid:

The compound of Ex. 38, Part E was converted to the correspondingprimary amidine via the amidoxime as described in Ex. 1, Part F.Subsequent saponification of the ethyl ester provided the titlecompound. LRMS(ESI) m/z 345.2 (100); HRMS for C₁₈H₂₅N₄O₃ 345.1926(calcd); 345.1915 (obs); ¹HNMR(D₂O) δ: 7.68(s, 4H); 4.82(m, 1H); 3.61(s,2H); 3.44(m, 3H); 3.05(m, 1H); 2.86(m, 2H); 1.89(m, 2H): 1.68(m, 2H):1.44(m, 3H) ppm.

EXAMPLE 392-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]piperidin-1-yl]aceticAcid

This compound was prepared from the compound of Ex. 38, Part E using aPinner reaction with morpholine to form the amidine followed byhydrolysis of the ester and HPLC purification as described under theprocedure for Ex.3. LRMS(ESI) m/z 415.3 (100); ¹HNMR(D₂O) δ: 7.70(d,J=8.5, 2H); 7.49(d, J=8.8, 2H); 4.82(m, 1H); 3.78(m, 2H); 3.64(m, 4H);3.49(m, 5H); 3.37(m, 2H); 3.05(m, 1H); 2.85(m, 2H); 1.89(m, 2H); 1.65(m,2H); 1.49(m, 3H) ppm.

EXAMPLE 402-[4-[3-[4-(cis-2,6-dimethylmorpholinoiminomethyl)phenyl]-isoxazolin-5-ylmethyl]piperidin-1-yl]aceticAcid

(cis-2,6-dimethylmorpholine) LRMS(ESI) m/z 443.3 (100). HRMS forC₂₄H₃₅N₄O₄ 443.2658 (calcd); 443.2659 (obs). ¹HNMR(D₂O) δ: 7.70(d,J=8.4, 2H); 7.499d, J=8.4, 2H); 4.80(m, 1H); 3.90(m, 3H); 3.66(s, 2H);3.53(m, 4H); 3.05(m, 2H); 2.93(m, 3H); l.91(m, 2H); 1.66(m, 2H); 1.44(m,3H); 1.12(d, J=6.2, 3H); 0.90(d, J=6.3, 3H) ppm

EXAMPLE 412-[4-[3-[4-(tetrahydroisoquinolinoiminomethyl)phenyl]-isoxazolin-5-ylmethyl]-piperidin-1-yl]aceticAcid

(tetrahydroisoquinoline) LRMS(ESI) m/z 461.3 (90); (m+2H)/2 231.3 (100)HRMS for C₂₇H₃₃N₄O₃ 461.2552 (calcd); 461.2557 (obs). ¹HNMR(D₂O) δ:7.72(m, 2H); 7.50(m, 2H); 7.15(m, 2H); 7.10-6.82(m, 2H, mixture ofrotomers); 4.80(m, 1H); 4.6(m, 3H); 4.41(s, 1H); 3.71(m, 1H); 3.62(s,2H); 3.46(m, 3H); 3.01(m, 2H); 2.90(m, 2H); 2.83(m, 1H); 1.90(m, 2H);1.70(m, 2H); 1.44(m,2H) ppm

EXAMPLE 72a2-[4-[3-[4-(tetrahydroisoquinolinoiminomethyl)phenyl]-isoxazolin-5(R)-ylmethyl]-piperazin-1-yl]aceticAcid

(tetrahydroisoquinoline) ¹H-NMR (300 MHz) δ 7.95 (2H, m) 7.70 (2H, m)7.30-7.15 (4H, m) 5.15 (1H, bm) 3.88 (1H, t, J=7.5 Hz) 3.73 (2H, s)3.68-3.60 (2H, m) 3.24-3.10 (1OH, m) 2.95 (1H, t, J=7.5 Hz). MS(M+H)⁻462.3. Anal. Calcd. For C₂₆H₃₁N₅O₃ +2.75TFA: C, 48.81; H, 4.39; N,9.04; F, 20.22. Found: C, 48.62; H, 4.32; N, 8.99; F, 20.45.

EXAMPLE 1002-[4-[[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-yl]carbonyl]piperazin-1-yl]aceticAcid

Part A: 1-t-butoxycarbonyl-4-allylcarbonylpiperazine:

Boc-piperazine (5.0 g (27 mmol) was dissolved in anhydrous N,N-dimethylformamide (30 mL) under a nitrogen atmosphere and the solutioncooled to 0° C. in an ice bath. Triethylamine (67 mmol) was added to thesolution followed by the dropwise addition of acryloyl chloride (30mmol). After complete addition of the acid chloride, the reaction wasallowed to come to room temperature and stirred 2.0-2.5 h. The reactionwas then diluted with 200 mL ethyl acetate and washed with water,followed by saturated sodium bicarbonate, 5% citric acid, and brine. Theorganic layer was dried over anhydrous sodium sulfate, filtered andevaporated. Purification of the resulting yellow oil on silica with 1:1hexane:ethyl acetate gave 2.09 g (8.7 mmol, 32%) of the desired product.¹H-NMR(CDCl₃) δ 6.56(1H, dd, J=16.7, 10.3); 6.31(1H, dd, J=16.7, 1.4);5.73(1H, dd, J=16.7, 1.8); 3.66-3.44(8H, m); 1.48(9H, s) ppm.

Part B:1-t-butoxycarbonyl-4-[3[4-cyanophenyl)isoxazolin-5-yl]carbonyl]-piperazine:

The compound of Ex. 100, Part A (2.09 g, 8.7 mmol) was dissolved in 25mL anhydrous methylene chloride and the compound of Ex. 12, Part B (1.57g, 8.7 mmol) was added. To this cloudy reaction mixture, a solution oftriethylamine (1.5 mL, 10 mmol) in methylene chloride (10 mL) was addeddrop by drop. The reaction was stirred at room temperature for 16 h, andthe solids were filtered, washed with methylene chloride, and thefiltrate evaporated under reduced pressure. The resulting residue wastaken up in ethyl acetate and washed with 5% citric acid solution,saturated sodium bicarbonate, and brine, dried over anhydrous sodiumsulfate and evaporated. Purification on silica gel using 1:1hexane:ethyl acetate gave 2.49 g (6.5 mmol, 74%) of the desired product.¹H-NMR(CDCl₃) δ 7.76(4H, dd, J=29.0, 8.8); 5.47-5.41(1H, m); 4.27(1H,dd, J=16.9, 7.3), 3.88-3.81(2H, m); 3.68-3.31(7H, m); 1.49(9H, s) ppm.

Part C: 4-[3-[4-cyanophenyl)isoxazolin-5-yl]carbonyl]-piperazineHydrochloride:

The compound of Ex. 100, Part B was taken up in anhydrous dioxane (25mL) and treated with 4.0N HCl in dioxane (20 mL) at room temperatureunder nitrogen. The reaction was stirred until disappearance of thestarting material was seen by tlc. The reaction mixture was diluted withether and the resulting precipitate was filtered, washed thoroughly withether and dried in vacuo to give 1.72 g (5.4 mmol, 82%) of the productas its hydrochloride salt. ¹H-NMR(CD₃OD) δ 7.83(4H, dd, J=25.1, 8.4);5.68-5.66(1H, m); 4.86-3.98(4H, m); 3.64-3.52(4H, m) ppm; MS 285.2(M+H)⁺.

Part D: Ethyl 4-[3-[4-cyanophenyl)isoxazolin-5-yl]carbonyl]-piperazinylAcetate:

The compound of Ex. 100, Part C (1.72 g, 5.4 mmol) was taken up inanhydrous N,N-dimethylformamide (15 mL) under nitrogen and was treatedwith potassium carbonate (2.22 g, 16 mmol) followed by dropwise additionof ethyl bromoacetate (0.895 g, 5.9 mmol). When no starting materialremained by tlc, the solution was diluted with ethyl acetate and washedwith water followed by saturated sodium bicarbonate solution and brine.The organic layer was dried over anhydrous sodium sulfate, filtered andevaporated to give 1.70 g (4.6 mmol, 86%) of the desired product.¹H-NMR(CDCl₃) δ 7.76(4H, dd, J=29.6, 8.4); 5.47-5.41(1H, m);4.30-4.09(3H, m); 3.94-3.85(2H, m); 3.70-3.54(2H, m); 3.37(1H, dd,J=16.8, 10.5); 2.82-2.49(4H,m); 1.29(3H, t, J=7.4) ppm.

Part E: Ethyl4-[3-[4-(n-butylaminoiminomethyl)phenyl]-isoxazolin-5-ylcarbonyl]piperazinylAcetate:

The compound of Ex. 100, Part D (1.70 g, 4.6 mmol) was taken up inethanol (50 mL) and cooled in an ice bath. HCl (g) was bubbled in to thesolution for 30 min and the reaction capped and allowed to come to roomtemperature and stand overnight. The solvents were then removed in vacuoand the residue triturated with ether, filtered and dried under vacuumto give 2.2 g of an off white solid a portion of which (0.70 g, 1.4mmol) was redissolved in ethanol and treated with n-butylamine (0.707mL, 7 mmol) under nitrogen at room temperature After 16 hr, the solventwas removed under reduced pressure and the resulting residue purified byreverse phase prep HPLC to give the desired product (0.217 g, 0.48mmol). ¹H-NMR (CD₃OD) δ 7.85(4H, dd, J=43.6, 8.4); 5.71-5.65(1H, m);4.31(2H, q, J=7.0); 4.19(2H, s); 4.10-4.00(4H, m); 3.65-3.41(8H, m);1.72(2H, q, J=7.7); 1.48(2H, q, J=7.7); 1.31(3H, t, J=7.3); 1.00(3H, t,J=7.3) ppm; MS (ES+) m/z 444.3 (M+H)⁺.

Part F:3-[4-[(N-n-butyl-N′-t-butoxycarbonyl)-aminoiminomethyl]phenyl]isoxazolin-5-ylcarboxylicAcid:

The compound obtained from Ex. 100, Part E (0.260 g, 0.6 mmol) wasdissolved in 6.0 N HCl (2.0 mL) and heated at reflux for 1.0-1.5 hr.Analysis of the crude reaction mixture indicated cleavage of the amidebond. The resulting acid was isolated after evaporation of the reactionmixture (0.150 g). MS 290.2 (M+H)⁺. This material was taken up intotetrahydrofuran and treated with sodium hydroxide (0.031 g, 0.77 mmol)followed by (BOC)₂O (0.168 g, 0.77 mmol) at room temperature under anitrogen atmosphere and reaction was stirred 16 hr. The solvent was thenevaporated and the residue taken up into water. The pH was adjusted with10% aqueous citric acid solution, so that the solution became cloudy,and the product was obtained by extraction with ethyl acetate.Evaporation of the solvent yielded the BOC protected amidine acid (0.107g, 0.28 mmol) which was used without further purification forcondensation with benzyl 4-piperazine acetate.

Part G: Benzyl 4-t-butoxycarbonyl-1-piperazinyl Acetate:

Boc-piperazine (1.0 g, 5.4 mmol) was taken up in anhydrous methylenechloride (15 mL) and treated with triethylamine (0.974 mL, 7.0 mmol)followed by benzyl bromoacetate (0.936 mL, 5.9 mmol). The reaction wasstirred overnight and the solvents were removed under vacuum. Theresulting residue was taken up into ethyl acetate and was washed with 5%citric acid solution followed by saturated sodium bicarbonate solutionand brine. After drying the organic layer over anhydrous sodium sulfateand evaporation of the solvent, the desired product was obtained (1.59g, 4.8 mmol). This product was taken up methylene chloride (qo mL) andtreated with TFA (5.0 mL). After stirring 1.0 hr, the solvents wereremoved in vacuo leaving the piperazine acetate as an orange oil (1.92g, 87%). lH-NMR(CD30D) δ 7.37-7.30(5H, m); 5.17(2H, s); 3.56(2H, s);3.50-3.24(4H, m); 3.00-2.96(4H, m); MS (ES+) m/z 235.2 (M+H)⁺.

Part H. Benzyl4-[[3-[4-(n-butylaminoiminomethyl)phenyl]-isoxazolin-5-yl]carbonyl]piperazinylAcetate:

The compound of Ex. 100, Part F was dissolved in anhydrousN,N-dimethylformamide (5.0 mL) and the compound of Ex. 100, Part G (0.28mmol), N-methyl morpholine (0.54 mmol) and BOP-reagent (0.42 mmol) wereadded. The reaction was stirred under nitrogen at room temperature for16 hrs then was diluted with ethyl acetate and washed with waterfollowed by saturated sodium bicarbonate, and brine. The oily residueresulting from evaporation of the solvent was purified by prep HPLCwhich also resulted in cleavage of Boc protecting group from the amidineto give the desired product (0.086 g, 0.17 mmol) ¹H-NMR(CD₃OD) δ7.84(4H, dd, J=43.0, 8.8); 7.41-7.34(5H, m); 5.68-5.64(1H, m); 5.29(2H,s); 4.24(2H, s); 4.07-3.93(4H, m); 3.60-3.28(8H, m); 1.73(2H, q, J=7.7);1.49(2H, q, J=7.7); 1.00(3H, t, J=7.4) ppm; MS (ES+) m/z 506.4 (M+H)⁺.

Part I:2-[4-[[3-[4-(n-butylaminoiminomethyl)phenyl]-isoxazolin-5-yl]carbonyl]piperazinyl]aceticAcid:

The compound of Ex. 100, Part H was dissolved in anhydrous methanol (3.0mL) and 1,4-cyclohexadiene (2.0 mL) and palladium hydroxide catalyst (20mg) was added. The whole was kept under nitrogen at reflux for 1.0-1.5hr. The reaction was then cooled and filtered through a pad of celite.The resulting filtrate was evaporated and the residue purified by prepHPLC to give the title compound (14 mg). ¹H-NMR(CD₃OD) δ 7.85(4H, dd,J=43.2, 8.5); 5.75-5.62(1H, m); 4.15(2H, s); 4.02-3.99(3H, m);3.61-3.41(9H, m); 1.71(2H, q, J=7.7); 1.46(2H, q, J=7.7); 1.00(3H, t,J=7.4) ppm; HRMS calc'd for C₂₁H₃₀N₅O₄: 416.2298. Found: 416.2305.

Using the methods outlined above the compounds of the following Tables1a-1k have been synthesized. Examples 42-71, 111-114, 121-123, 131-133,141-146, 151-156, 161, 171 800a, and 802x, were synthesized by oneskilled in the art of organic synthesis using the principles disclosedabove with the appropriate starting materials. It is understood that oneskilled in the art of organic synthesis can readily synthesize Examples42-71, 111-114, 121-123, 131-133, 141-146, 151-156, 161, 171 , 962a, and874x, by applying the synthetic principles disclosed above with theappropriate starting materials.

TABLE 1a

MS Ex. # R²R^(2b)N— G R⁷ (M + 1)  1 H₂N— CR⁷ OH 361.18  2 H₂N— CR⁷OCH₂CO₂H 419.3  3 morpholino CR⁷ OCH₂CO₂H 489.23  3a** morpholino CR⁷OCH₂CO₂H 489.23  3b* morpholino CR⁷ OCH₂CO₂H 489.23  4 (CH₃CH₂CH₂CH₂)HN—CR⁷ OCH₂CO₂H 475.4  5 2,6-dimethylmorpholino CR⁷ OCH₂CO₂H 517.2  64-methylpiperazino CR⁷ OCH₂CO₂H 502.4  7 piperidino CR⁷ OCH₂CO₂H 487.3 8 4-phenylpiperazino CR⁷ OCH₂CO₂H 564.4  9 thiomorpholino CR⁷ OCH₂CO₂H505.2 10* cis-2,6-dimethylmorpholino CR⁷ OCH₂CO₂H 517.2 11tetrahydroisoquinolino CR⁷ OCH₂CO₂H 535.4 12 morpholino N — 416.1 13(CH₃CH₂CH₂CH₂)HN— N — 402.3 14 H₂N— N — 346.3 15 N-methylpiperazino N —429.3 16 cis-2,6-dimethylmorpholino N — 444.3 16a**cis-2,6-dimethylmorpholino N — 444.3 17 1,4-dioxa-8-azaspiro[4.5]decyl N— 472.2 18 N-phenylpiperazino N — 491.3 19 cis-3,5-dimethylpiperazino N— 443.3 20 4-(2-fluorophenyl)piperazino N — 509.3 214-(2-methylphenyl)piperazino N — 505.3 22* morpholino N — 416.2 23**morpholino N — 416.2 24 2-(4-pyridyl)ethylamino N — 451.4 24a**2-(4-pyridyl)ethylamino N — 451.4 25 phenethylamino N — 450.3 26((CH₃)₂CHCH₂)HN— N — 402.3 27 (cyclopropylmethyl)HN— N — 400.3 28(propargyl)HN— N — 384.3 29 (CH₃CH₂)₂N— N — 402.3 30 (benzyl)(CH₃)N— N —450.3 31 (phenethyl)(CH₃)N— N — 464.3 31a** (phenethyl)(CH₃)N— N — 464.332 (4-pyridyl)methylamino N — 437.3 33 2-(2-pyridyl)ethylamino N — 451.434 1-naphthylmethylamino N — 486.3 35 (2-pyridyl)methylamino N — 437.336 (CH₃CH₂)(CH₃)N— N — 388.3 37 H₂N— CR⁷ OCH₂C₆H₅ 451.3 38 H₂N— CR⁷ H345.2 39 morpholino CR⁷ H 415.3 40 cis-2,6-dimethylmorpholino CR⁷ H443.3 40a^(♦) cis-2,6-dimethylmorpholino CR⁷ H 443.3 40b^(♦♦)cis-2,6-dimethylmorpholino CR⁷ H 443.3 41^(♦) tetrahydroisoquinolino CR⁷H 461.4 42^(♦♦) tetrahydroisoquinolino CR⁷ H 461.4 43^(♦♦)tetrahydroisoquinolino CR⁷ OCH₂CO₂H 535.2 44 tetrahydroisoquinolino CR⁷OCH₂C₆H₅ 535.2 45 benzylamino N — 436.2 46 2,2-diphenylethylamino N —526.3 47 (3-pyridyl)ethylamino N — 451.2 48 (3-pyridyl)methylamino N —437.3 49 4-chlorophenethylamino N — 484.3 50 4-imidazolylethylamino N —440.3 51 4-aminosulfonylphenethylamino N — 529.3 524-fluorophenethylamino N — 468.3 53 4-methoxyphenethylamino N — 480.3 542-indanoyl N — 462.3 55 7- N — 492.2 methoxy-tetrahydroisoquinolino 563,4- N — 494.3 methylenedioxyphenethylamino 57 6,7-dimethoxytetrahydro-N — 522.3 isoquinolino 58 6- N — 492.2 methoxytetrahydroisoquinolino 598- N — 492.2 methoxytetrahydroisoquinolino 607-chlorotetrahydroisoquinolino N — 496.2 61 5- N — 492.2methoxytetrahydroisoquinolino 62 6,7-methylenedioxytetrahydro- N — 506.1isoquinolino 63 7-fluorotetrahydroisoquinolino N — 480.2 64N-benyzlpiperazino N — 505.3 65 isopentylNH— N — 416.3 66N-(2-pyridyl)piperazino N — 492.3 67**

N — 498.3 68** 7-methylsulfonylamino- N — 555.2 tetrahydroisoquinolino69** 5-methylsulfonylamino- N — 555.2 tetrahydroisoquinolino 70**5-acetylamino- N — 519.3 tetrahydroisoquinolino 71**7-phenylsulfonylamino- N — 617.3 tetrahydroisoquinolino 72*tetrahydroisoquinolino N — 462.3 72a** tetrahydroisoquinolino N — 462.3*single enantiomer at isoxazoline (S) **single enantiomer at isoxazoline(R) ^(♦)single enantiomer at isoxazoline (−) ^(♦♦)single enantiomer atisoxazoline (+)

TABLE 1b

Ex. # R²R^(2b)N— G R⁷ MS (M + 1) 100 (CH₃CH₂CH₂CH₂)HN— N — 416.23

TABLE 1c

Ex. # R²R^(2b)N— MS (M + 1) 111 H₂N— 360.2 112 2-(4-pyridyl)ethylamino465.3 113 Tetrahydroisoquinolino 476.3 114 cis-2,6-dimethylmorpholino458.3

TABLE 1d

Ex. # R²R^(2b)N— MS (M + 1) 121 H₂N— 360.2 122 Tetrahydroisoquinolino476.2 123 Cis-2,6-dimethylmorpholino 458.2

TABLE 1e

Ex. # R²R^(2b)N— MS (M + 1) 131 H₂N— 344.3 132 Tetrahydroisoquinolino460.2 133 Cis-2,6-dimethylmorpholino 442.2

TABLE 1f

Ex. # R²R^(2b)N— a b MS (M + 1) 141 n-butyl-NH— single double 448.3 142cis-2,6-dimethylmorpholino single double 441.3 143tetrahydroisoquinolino double single 459.2 144 H₂N— double single 343.2145 cis-2,6-dimethylmorpholino double single 441.4 146 n-butyl-NH—double single 448.2

TABLE 1g

Ex. # R²R^(2b)N— MS (M + H) 151 2-(4-pyridyl)ethyl-NH— 465.2 152phenethyl-NH— 464.2 153 cis-2,6-dimethylmorpholino 458.3 154 H₂N— 360.2155 morpholino 430.2 156 tetrahydroisoquinolino 476.2

TABLE 1h

Ex. # R²R^(2b)N— G R⁷ MS (M + 1) 161 H₂N— CR⁷ H 353.2

TABLE 1i

Ex. # R²R^(2b)N— G R⁷ MS (M + 1) 171 H₂N— N — 374.3

TABLE 1k

Ex. # R²R^(2b)N— G R⁷ W^(b) m MS (M + 1) 962a H₂N— N — —H 1 360.2 874xmorpholino N — —CH₂Ph 0 506.4

The following Tables 2 and 3 contain representative examples of thepresent invention. At the start of each table is one formula followed byspecies a through rr demonstrating the intended substitution ofR²R^(2b)N(N═)C(phenyl)-. Each entry in each table is intended to bepaired with each formulae at the start of the table. For example,Example 100 in Table 2 is intended to be paired with each of formulae a,b, c, d, . . . through rr of Table 2, thereby representing Example 100a,100b, 100c, etc. Example 500, and so on, in Table 3 is intended to bepaired with each of formula of Table 3 following the a through rrsubstitution of R²R^(2b)N(N=)C(phenyl)- in Table 2.

TABLE 2

Ex. # R²R^(2b)N(N)Cphenyl- G R⁷ W^(a) 200 a-rr CR⁷ —H H— 201 a-rr CR⁷ —H(ethyl)SO₂NH— 202 a-rr CR⁷ —H (n-propyl)SO₂NH— 203 a-rr CR⁷ —H(n-butyl)SO₂NH— 204 a-rr CR⁷ —H (phenyl)SO₂NH— 205 a-rr CR⁷ —H(4-Me-phenyl)SO₂NH— 206 a-rr CR⁷ —H (3-Me-phenyl)SO₂NH— 207 a-rr CR⁷ —H(2-Me-phenyl)SO₂NH— 208 a-rr CR⁷ —H (4-Br-phenyl)SO₂NH— 209 a-rr CR⁷ —H(4-Cl-phenyl)SO₂NH— 210 a-rr CR⁷ —H (4-F-phenyl)SO₂NH— 211 a-rr CR⁷ —H(3-Br-phenyl)SO₂NH— 212 a-rr CR⁷ —H (3-Cl-phenyl)SO₂NH— 213 a-rr CR⁷ —H(3-F-phenyl)SO₂NH— 214 a-rr CR⁷ —H (2-Br-phenyl)SO₂NH— 215 a-rr CR⁷ —H(2-Cl-phenyl)SO₂NH— 216 a-rr CR⁷ —H (2-F-phenyl)SO₂NH— 217 a-rr CR⁷ —H(4-F₃C-phenyl)SO₂NH— 218 a-rr CR⁷ —H (3-F₃C-phenyl)SO₂NH— 219 a-rr CR⁷—H (2-F₃C-phenyl)SO₂NH— 220 a-rr CR⁷ —H (4-MeO-phenyl)SO₂NH— 221 a-rrCR⁷ —H (4-cyano-phenyl)SO₂NH— 222 a-rr CR⁷ —H (4-propyl-phenyl)SO₂NH—223 a-rr CR⁷ —H (4-i-propyl-phenyl)SO₂NH— 224 a-rr CR⁷ —H(4-butyloxyphenyl)SO₂NH— 225 a-rr CR⁷ —H (benzyl)SO₂NH— 226 a-rr CR⁷ —H(phenylethyl)SO₂NH— 227 a-rr CR⁷ —H (phenylpropyl)SO₂NH— 228 a-rr CR⁷ —H(2-pyridyl)SO₂NH— 229 a-rr CR⁷ —H (3-pyridyl)SO₂NH— 230 a-rr CR⁷ —H(4-pyridyl)SO₂NH— 231 a-rr CR⁷ —H (2-thienyl)SO₂NH— 232 a-rr CR⁷ —H(2,4,6-Me₃-phenyl)SO₂NH— 233 a-rr CR⁷ —H (3,5-Me₂-isoxazolyl)SO₂NH— 234a-rr CR⁷ —H (ethyl)OCONH— 235 a-rr CR⁷ —H (n-propyl)OCONH— 236 a-rr CR⁷—H (i-propyl)OCONH— 237 a-rr CR⁷ —H (n-butyl)OCONH— 238 a-rr CR⁷ —H(i-butyl)OCONH— 239 a-rr CR⁷ —H (t-butyl)OCONH— 240 a-rr CR⁷ —H(benzyl)OCONH— 241 a-rr CR⁷ —H (4-Me-benzyl)OCONH— 242 a-rr CR⁷ —H(4-MeO-benzyl)OCONH— 243 a-rr CR⁷ —H (4-Br-benzyl)OCONH— 244 a-rr CR⁷ —H(4-F-benzyl)OCONH— 245 a-rr CR⁷ —H (4-Cl-benzyl)OCONH— 246 a-rr CR⁷ —H(4-phenoxybenzyl)OCONH— 247 a-rr CR⁷ —H (2-pyridylmethyl)OCONH— 248 a-rrCR⁷ —H (3-pyridylmethyl)OCONH— 249 a-rr CR⁷ —H (4-pyridylmethyl)OCONH—250 a-rr CR⁷ —H (cyclopropylethyl)OCONH— 251 a-rr CR⁷ —H(cyclopropylmethyl)OCONH— 252 a-rr CR⁷ —H (ethyl)CONH— 253 a-rr CR⁷ —H(n-propyl)CONH— 254 a-rr CR⁷ —H (i-propyl)CONH— 255 a-rr CR⁷ —H(n-butyl)CONH— 256 a-rr CR⁷ —H (i-butyl)CONH— 257 a-rr CR⁷ —H(t-butyl)CONH— 258 a-rr CR⁷ —H (benzyl)CONH— 259 a-rr CR⁷ —H(4-Me-benzyl)CONH— 260 a-rr CR⁷ —H (4-MeO-benzyl)CONH— 261 a-rr CR⁷ —H(4-Br-benzyl)CONH— 262 a-rr CR⁷ —H (4-F-benzyl)CONH— 263 a-rr CR⁷ —H(4-Cl-benzyl)CONH— 264 a-rr CR⁷ —H (4-phenoxybenzyl)CONH— 265 a-rr CR⁷—H (2-pyridyimethyl)CONH— 266 a-rr CR⁷ —H (3-pyridylmethyl)CONH— 267a-rr CR⁷ —H (4-pyridylmethyl)CONH— 268 a-rr CR⁷ —H(cyclopropylethyl)CONH— 269 a-rr CR⁷ —H (cyclopropylmethyl)CONH— 270a-rr CR⁷ —H (ethyl)NHCONH— 271 a-rr CR⁷ —H (n-propyl)NHCONH— 272 a-rrCR⁷ —H (i-propyl)NHCONH— 273 a-rr CR⁷ —H (n-butyl)NHCONH— 274 a-rr CR⁷—H (i-butyl)NHCONH— 275 a-rr CR⁷ —H (t-butyl)NHCONH— 276 a-rr CR⁷ —H(benzyl)NHCONH— 277 a-rr CR⁷ —H (4-Me-benzyl)NHCONH— 278 a-rr CR⁷ —H(4-Meo-benzyl)NHCONH— 279 a-rr CR⁷ —H (4-Br-benzyl)NHCONH— 280 a-rr CR⁷—H (4-F-benzyl)NHCONH— 281 a-rr CR⁷ —H (4-Cl-benzyl)NHCONH— 282 a-rr CR⁷—H (4-phenoxybenzyl)NHCONH— 283 a-rr CR⁷ —H (2-pyridylmethyl)NHCONH— 284a-rr CR⁷ —H (3-pyridylmethyl)NHCONH— 285 a-rr CR⁷ —H(4-pyridylmethyl)NHCONH— 286 a-rr CR⁷ —H (cyclopropylethyl)NHCONH— 287a-rr CR⁷ —H (cyclopropylmethyl)NHCONH 288 a-rr CR⁷ —OH —H 289 a-rr CR⁷—OH (ethyl)SO₂NH— 290 a-rr CR⁷ —OH (n-propyl)SO₂NH— 291 a-rr CR⁷ —OH(n-butyl)SO₂NH— 292 a-rr CR⁷ —OH (phenyl)SO₂NH— 293 a-rr CR⁷ —OH(4-Me-phenyl)SO₂NH— 294 a-rr CR⁷ —OH (3-Me-phenyl)SO₂NH— 295 a-rr CR⁷—OH (2-Me-phenyl)SO₂NH— 296 a-rr CR⁷ —OH (4-Br-phenyl)SO₂NH— 297 a-rrCR⁷ —OH (4-Cl-phenyl)SO₂NH— 298 a-rr CR⁷ —OH (4-F-phenyl)SO₂NH— 299 a-rrCR⁷ —OH (3-Br-phenyl)SO₂NH— 300 a-rr CR⁷ —OH (3-Cl-phenyl)SO₂NH— 301a-rr CR⁷ —OH (3-F-phenyl)SO₂NH— 302 a-rr CR⁷ —OH (2-Br-phenyl)SO₂NH— 303a-rr CR⁷ —OH (2-Cl-phenyl)SO₂NH— 304 a-rr CR⁷ —OH (2-F-phenyl)SO₂NH— 305a-rr CR⁷ —OH (4-F₃C-phenyl)SO₂NH— 306 a-rr CR⁷ —OH (3-F₃C-phenyl)SO₂NH—307 a-rr CR⁷ —OH (2-F₃C-phenyl)SO₂NH— 308 a-rr CR⁷ —OH(4-MeO-phenyl)SO₂NH— 309 a-rr CR⁷ —OH (4-cyano-phenyl)SO₂NH— 310 a-rrCR⁷ —OH (4-propyl-phenyl)SO₂NH— 311 a-rr CR⁷ —OH(4-i-propyl-phenyl)SO₂NH— 312 a-rr CR⁷ —OH (4-butyloxyphenyl)SO₂NH— 313a-rr CR⁷ —OH (benzyl)SO₂NH— 314 a-rr CR⁷ —OH (phenylethyl)SO₂NH— 315a-rr CR⁷ —OH (phenylpropyl)SO₂NH— 316 a-rr CR⁷ —OH (2-pyridyl)SO₂NH— 317a-rr CR⁷ —OH (3-pyridyl)SO₂NH— 318 a-rr CR⁷ —OH (4-pyridyl)SO₂NH— 319a-rr CR⁷ —OH (2-thienyl)SO₂NH— 320 a-rr CR⁷ —OH (2,4,6-Me₃-phenyl)SO₂NH—321 a-rr CR⁷ —OH (3,5-Me₂-isoxazolyl)SO₂NH— 322 a-rr CR⁷ —OH(ethyl)OCONH— 323 a-rr CR⁷ —OH (n-propyl)OCONH— 324 a-rr CR⁷ —OH(i-propyl)OCONH— 325 a-rr CR⁷ —OH (n-butyl)OCONH— 326 a-rr CR⁷ —OH(i-butyl)OCONH— 327 a-rr CR⁷ —OH (t-butyl)OCONH— 328 a-rr CR⁷ —OH(benzyl)OCONH— 329 a-rr CR⁷ —OH (4-Me-benzyl)OCONH— 330 a-rr CR⁷ —OH(4-Meo-benzyl)OCONH— 331 a-rr CR⁷ —OH (4-Br-benzyl)OCONH— 332 a-rr CR⁷—OH (4-F-benzyl)OCONH— 333 a-rr CR⁷ —OH (4-Cl-benzyl)OCONH— 334 a-rr CR⁷—OH (4-phenoxybenzyl)OCONH— 335 a-rr CR⁷ —OH (2-pyridylmethyl)OCONH— 336a-rr CR⁷ —OH (3-pyridylmethyl)OCONH— 337 a-rr CR⁷ —OH(4-pyridylmethyl)OCONH— 338 a-rr CR⁷ —OH (cyclopropylethyl)OCONH— 339a-rr CR⁷ —OH (cyclopropylmethyl)OCONH— 340 a-rr CR⁷ —OH (ethyl)CONH— 341a-rr CR⁷ —OH (n-propyl)CONH— 342 a-rr CR⁷ —OH (i-propyl)CONH— 343 a-rrCR⁷ —OH (n-butyl)CONH— 344 a-rr CR⁷ —OH (i-butyl)CONH— 345 a-rr CR⁷ —OH(t-butyl)CONH— 346 a-rr CR⁷ —OH (benzyl)CONH— 347 a-rr CR⁷ —OH(4-Me-benzyl)CONH— 348 a-rr CR⁷ —OH (4-MeO-benzyl)CONH— 349 a-rr CR⁷ —OH(4-Br-benzyl)CONH— 350 a-rr CR⁷ —OH (4-F-benzyl)CONH— 351 a-rr CR⁷ —OH(4-Cl-benzyl)CONH— 352 a-rr CR⁷ —OH (4-phenoxybenzyl)CONH— 353 a-rr CR⁷—OH (2-pyridylmethyl)CONH— 354 a-rr CR⁷ —OH (3-pyridylmethyl)CONH— 355a-rr CR⁷ —OH (4-pyridylmethyl)CONH— 356 a-rr CR⁷ —OH(cyclopropylethyl)CONH— 357 a-rr CR⁷ —OH (cyclopropylmethyl)CONH— 358a-rr CR⁷ —OH (ethyl)NHCONH— 359 a-rr CR⁷ —OH (n-propyl)NHCONH— 360 a-rrCR⁷ —OH (i-propyl)NHCONH— 361 a-rr CR⁷ —OH (n-butyl)NHCONH— 362 a-rr CR⁷—OH (i-butyl)NHCONH— 363 a-rr CR⁷ —OH (t-butyl)NHCONH— 364 a-rr CR⁷ —OH(benzyl)NHCONH— 365 a-rr CR⁷ —OH (4-Me-benzyl)NHCONH— 366 a-rr CR⁷ —OH(4-Meo-benzyl)NHCONH— 367 a-rr CR⁷ —OH (4-Br-benzyl)NHCONH— 368 a-rr CR⁷—OH (4-F-benzyl)NHCONH— 369 a-rr CR⁷ —OH (4-Cl-benzyl)NHCONH— 370 a-rrCR⁷ —OH (4-phenoxybenzyl)NHCONH— 371 a-rr CR⁷ —OH(2-pyridylmethyl)NHCONH— 372 a-rr CR⁷ —OH (3-pyridylmethyl)NHCONH— 373a-rr CR⁷ —OH (4-pyridylmethyl)NHCONH— 374 a-rr CR⁷ —OH(cyclopropylethyl)NHCONH— 375 a-rr CR⁷ —OH (cyclopropylmethyl)NHCONH 376a-rr CR⁷ —OCH₂CO₂H —H 377 a-rr CR⁷ —OCH₂CO₂H (ethyl)SO₂NH— 378 a-rr CR⁷—OCH₂CO₂H (n-propyl)SO₂NH— 379 a-rr CR⁷ —OCH₂CO₂H (n-butyl)SO₂NH— 380a-rr CR⁷ —OCH₂CO₂H (phenyl)SO₂NH— 381 a-rr CR⁷ —OCH₂CO₂H(4-Me-phenyl)SO₂NH— 382 a-rr CR⁷ —OCH₂CO₂H (3-Me-phenyl)SO₂NH— 383 a-rrCR⁷ —OCH₂CO₂H (2-Me-phenyl)SO₂NH— 384 a-rr CR⁷ —OCH₂CO₂H(4-Br-phenyl)SO₂NH— 385 a-rr CR⁷ —OCH₂CO₂H (4-Cl-phenyl)SO₂NH— 386 a-rrCR⁷ —OCH₂CO₂H (4-F-phenyl)SO₂NH— 387 a-rr CR⁷ —OCH₂CO₂H(3-Br-phenyl)SO₂NH— 388 a-rr CR⁷ —OCH₂CO₂H (3-Cl-phenyl)SO₂NH— 389 a-rrCR⁷ —OCH₂CO₂H (3-F-phenyl)SO₂NH— 390 a-rr CR⁷ —OCH₂CO₂H(2-Br-phenyl)SO₂NH— 391 a-rr CR⁷ —OCH₂CO₂H (2-Cl-phenyl)SO₂NH— 392 a-rrCR⁷ —OCH₂CO₂H (2-F-phenyl)SO₂NH— 393 a-rr CR⁷ —OCH₂CO₂H(4-F₃C-phenyl)SO₂NH— 394 a-rr CR⁷ —OCH₂CO₂H (3-F₃C-phenyl)SO₂NH— 395a-rr CR⁷ —OCH₂CO₂H (2-F₃C-phenyl)SO₂NH— 396 a-rr CR⁷ —OCH₂CO₂H(4-MeO-phenyl)SO₂NH— 397 a-rr CR⁷ —OCH₂CO₂H (4-cyano-phenyl)SO₂NH— 398a-rr CR⁷ —OCH₂CO₂H (4-propyl-phenyl)SO₂NH— 399 a-rr CR⁷ —OCH₂CO₂H(4-i-propyl-phenyl)SO₂NH— 400 a-rr CR⁷ —OCH₂CO₂H(4-butyloxyphenyl)SO₂NH— 401 a-rr CR⁷ —OCH₂CO₂H (benzyl)SO₂NH— 402 a-rrCR⁷ —OCH₂CO₂H (phenylethyl)SO₂NH— 403 a-rr CR⁷ —OCH₂CO₂H(phenylpropyl)SO₂NH— 404 a-rr CR⁷ —OCH₂CO₂H (2-pyridyl)SO₂NH— 405 a-rrCR⁷ —OCH₂CO₂H (3-pyridyl)SO₂NH— 406 a-rr CR⁷ —OCH₂CO₂H (4-pyridyl)SO₂NH—407 a-rr CR⁷ —OCH₂CO₂H (2-thienyl)SO₂NH— 408 a-rr CR⁷ —OCH₂CO₂H(2,4,6-Me₃-phenyl)SO₂NH— 409 a-rr CR⁷ —OCH₂CO₂H(3,5-Me₂-isoxazolyl)SO₂NH— 410 a-rr CR⁷ —OCH₂CO₂H (ethyl)OCONH— 411 a-rrCR⁷ —OCH₂CO₂H (n-propyl)OCONH— 412 a-rr CR⁷ —OCH₂CO₂H (i-propyl)OCONH—413 a-rr CR⁷ —OCH₂CO₂H (n-butyl)OCONH— 414 a-rr CR⁷ —OCH₂CO₂H(i-butyl)OCONH— 415 a-rr CR⁷ —OCH₂CO₂H (t-butyl)OCONH— 416 a-rr CR⁷—OCH₂CO₂H (benzyl)OCONH— 417 a-rr CR⁷ —OCH₂CO₂H (4-Me-benzyl)OCONH— 418a-rr CR⁷ —OCH₂CO₂H (4-MeO-benzyl)OCONH— 419 a-rr CR⁷ —OCH₂CO₂H(4-Br-benzyl)OCONH— 420 a-rr CR⁷ —OCH₂CO₂H (4-F-benzyl)OCONH— 421 a-rrCR⁷ —OCH₂CO₂H (4-Cl-benzyl)OCONH— 422 a-rr CR⁷ —OCH₂CO₂H(4-phenoxybenzyl)OCONH— 423 a-rr CR⁷ —OCH₂CO₂H (2-pyridylmethyl)OCONH—424 a-rr CR⁷ —OCH₂CO₂H (3-pyridylmethyl)OCONH— 425 a-rr CR⁷ —OCH₂CO₂H(4-pyridylmethyl)OCONH— 426 a-rr CR⁷ —OCH₂CO₂H (cyclopropylethyl)OCONH—427 a-rr CR⁷ —OCH₂CO₂H (cyclopropylmethyl)OCONH— 428 a-rr CR⁷ —OCH₂CO₂H(ethyl)CONH— 429 a-rr CR⁷ —OCH₂CO₂H (n-propyl)CONH— 430 a-rr CR⁷—OCH₂CO₂H (i-propyl)CONH— 431 a-rr CR⁷ —OCH₂CO₂H (n-butyl)CONH— 432 a-rrCR⁷ —OCH₂CO₂H (i-butyl)CONH— 433 a-rr CR⁷ —OCH₂CO₂H (t-butyl)CONH— 434a-rr CR⁷ —OCH₂CO₂H (benzyl)CONH— 435 a-rr CR⁷ —OCH₂CO₂H(4-Me-benzyl)CONH— 436 a-rr CR⁷ —OCH₂CO₂H (4-MeO-benzyl)CONH— 437 a-rrCR⁷ —OCH₂CO₂H (4-Br-benzyl)CONH— 438 a-rr CR⁷ —OCH₂CO₂H(4-F-benzyl)CONH— 439 a-rr CR⁷ —OCH₂CO₂H (4-Cl-benzyl)CONH— 440 a-rr CR⁷—OCH₂CO₂H (4-phenoxybenzyl)CONH— 441 a-rr CR⁷ —OCH₂CO₂H(2-pyridylmethyl)CONH— 442 a-rr CR⁷ —OCH₂CO₂H (3-pyridylmethyl)CONH— 443a-rr CR⁷ —OCH₂CO₂H (4-pyridylmethyl)CONH— 444 a-rr CR⁷ —OCH₂CO₂H(cyclopropylethyl)CONH— 445 a-rr CR⁷ —OCH₂CO₂H (cyclopropylmethyl)CONH—446 a-rr CR⁷ —OCH₂CO₂H (ethyl)NHCONH— 447 a-rr CR⁷ —OCH₂CO₂H(n-propyl)NHCONH— 448 a-rr CR⁷ —OCH₂CO₂H (i-propyl)NHCONH— 449 a-rr CR⁷—OCH₂CO₂H (n-butyl)NHCONH— 450 a-rr CR⁷ —OCH₂CO₂H (i-butyl)NHCONH— 451a-rr CR⁷ —OCH₂CO₂H (t-butyl)NHCONH— 452 a-rr CR⁷ —OCH₂CO₂H(benzyl)NHCONH— 453 a-rr CR⁷ —OCH₂CO₂H (4-Me-benzyl)NHCONH— 454 a-rr CR⁷—OCH₂CO₂H (4-Meo-benzyl)NHCONH— 455 a-rr CR⁷ —OCH₂CO₂H(4-Br-benzyl)NHCONH— 456 a-rr CR⁷ —OCH₂CO₂H (4-F-benzyl)NHCONH— 457 a-rrCR⁷ —OCH₂CO₂H (4-Cl-benzyl)NHCONH— 458 a-rr CR⁷ —OCH₂CO₂H(4-phenoxybenzyl)NHCONH— 459 a-rr CR⁷ —OCH₂CO₂H (2-pyridylmethyl)NHCONH—460 a-rr CR⁷ —OCH₂CO₂H (3-pyridylmethyl)NHCONH— 461 a-rr CR⁷ —OCH₂CO₂H(4-pyridylmethyl)NHCONH— 462 a-rr CR⁷ —OCH₂CO₂H(cyclopropylethyl)NHCONH— 463 a-rr CR⁷ —OCH₂CO₂H(cyclopropylmethyl)NHCONH 464 a-rr CR⁷ —OCH₂C₆H₅ —H 465 a-rr CR⁷—OCH₂C₆H₅ (ethyl)SO₂NH— 466 a-rr CR⁷ —OCH₂C₆H₅ (n-propyl)SO₂NH— 467 a-rrCR⁷ —OCH₂C₆H₅ (n-butyl)SO₂NH— 468 a-rr CR⁷ —OCH₂C₆H₅ (phenyl)SO₂NH— 469a-rr CR⁷ —OCH₂C₆H₅ (4-Me-phenyl)SO₂NH— 470 a-rr CR⁷ —OCH₂C₆H₅(3-Me-phenyl)SO₂NH— 471 a-rr CR⁷ —OCH₂C₆H₅ (2-Me-phenyl)SO₂NH— 472 a-rrCR⁷ —OCH₂C₆H₅ (4-Br-phenyl)SO₂NH— 473 a-rr CR⁷ —OCH₂C₆H₅(4-Cl-phenyl)SO₂NH— 474 a-rr CR⁷ —OCH₂C₆H₅ (4-F-phenyl)SO₂NH— 475 a-rrCR⁷ —OCH₂C₆H₅ (3-Br-phenyl)SO₂NH— 476 a-rr CR⁷ —OCH₂C₆H₅(3-Cl-phenyl)SO₂NH— 477 a-rr CR⁷ —OCH₂C₆H₅ (3-F-phenyl)SO₂NH— 478 a-rrCR⁷ —OCH₂C₆H₅ (2-Br-phenyl)SO₂NH— 479 a-rr CR⁷ —OCH₂C₆H₅(2-Cl-phenyl)SO₂NH— 480 a-rr CR⁷ —OCH₂C₆H₅ (2-F-phenyl)SO₂NH— 481 a-rrCR⁷ —OCH₂C₆H₅ (4-F₃C-phenyl)SO₂NH— 482 a-rr CR⁷ —OCH₂C₆H₅(3-F₃C-phenyl)SO₂NH— 483 a-rr CR⁷ —OCH₂C₆H₅ (2-F₃C-phenyl)SO₂NH— 484a-rr CR⁷ —OCH₂C₆H₅ (4-MeO-phenyl)SO₂NH— 485 a-rr CR⁷ —OCH₂C₆H₅(4-cyano-phenyl)SO₂NH— 486 a-rr CR⁷ —OCH₂C₆H₅ (4-propyl-phenyl)SO₂NH—487 a-rr CR⁷ —OCH₂C₆H₅ (4-i-propyl-phenyl)SO₂NH— 488 a-rr CR⁷ —OCH₂C₆H₅(4-butyloxyphenyl)SO₂NH— 489 a-rr CR⁷ —OCH₂C₆H₅ (benzyl)SO₂NH— 490 a-rrCR⁷ —OCH₂C₆H₅ (phenylethyl)SO₂NH— 491 a-rr CR⁷ —OCH₂C₆H₅(phenylpropyl)SO₂NH— 492 a-rr CR⁷ —OCH₂C₆H₅ (2-pyridyl)SO₂NH— 493 a-rrCR⁷ —OCH₂C₆H₅ (3-pyridyl)SO₂NH— 494 a-rr CR⁷ —OCH₂C₆H₅ (4-pyridyl)SO₂NH—495 a-rr CR⁷ —OCH₂C₆H₅ (2-thienyl)SO₂NH— 496 a-rr CR⁷ —OCH₂C₆H₅(2,4,6-Me₃-phenyl)SO₂NH— 497 a-rr CR⁷ —OCH₂C₆H₅(3,5-Me₂-isoxazolyl)SO₂NH— 498 a-rr CR⁷ —OCH₂C₆H₅ (ethyl)OCONH— 499 a-rrCR⁷ —OCH₂C₆H₅ (n-propyl)OCONH— 500 a-rr CR⁷ —OCH₂C₆H₅ (i-propyl)OCONH—501 a-rr CR⁷ —OCH₂C₆H₅ (n-butyl)OCONH— 502 a-rr CR⁷ —OCH₂C₆H₅(i-butyl)OCONH— 503 a-rr CR⁷ —OCH₂C₆H₅ (t-butyl)OCONH— 504 a-rr CR⁷—OCH₂C₆H₅ (benzyl)OCONH— 505 a-rr CR⁷ —OCH₂C₆H₅ (4-Me-benzyl)OCONH— 506a-rr CR⁷ —OCH₂C₆H₅ (4-MeO-benzyl)OCONH— 507 a-rr CR⁷ —OCH₂C₆H₅(4-Br-benzyl)OCONH— 508 a-rr CR⁷ —OCH₂C₆H₅ (4-F-benzyl)OCONH— 509 a-rrCR⁷ —OCH₂C₆H₅ (4-Cl-benzyl)OCONH— 510 a-rr CR⁷ —OCH₂C₆H₅(4-phenoxybenzyl)OCONH— 511 a-rr CR⁷ —OCH₂C₆H₅ (2-pyridylmethyl)OCONH—512 a-rr CR⁷ —OCH₂C₆H₅ (3-pyridylmethyl)OCONH— 513 a-rr CR⁷ —OCH₂C₆H₅(4-pyridylmethyl)OCONH— 514 a-rr CR⁷ —OCH₂C₆H₅ (cyclopropylethyl)OCONH—515 a-rr CR⁷ —OCH₂C₆H₅ (cyclopropylmethyl)OCONH— 516 a-rr CR⁷ —OCH₂C₆H₅(ethyl)CONH— 517 a-rr CR⁷ —OCH₂C₆H₅ (n-propyl)CONH— 518 a-rr CR⁷—OCH₂C₆H₅ (i-propyl)CONH— 519 a-rr CR⁷ —OCH₂C₆H₅ (n-butyl)CONH— 520 a-rrCR⁷ —OCH₂C₆H₅ (i-butyl)CONH— 521 a-rr CR⁷ —OCH₂C₆H₅ (t-butyl)CONH— 522a-rr CR⁷ —OCH₂C₆H₅ (benzyl)CONH— 523 a-rr CR⁷ —OCH₂C₆H₅(4-Me-benzyl)CONH— 524 a-rr CR⁷ —OCH₂C₆H₅ (4-MeO-benzyl)CONH— 525 a-rrCR⁷ —OCH₂C₆H₅ (4-Br-benzyl)CONH— 526 a-rr CR⁷ —OCH₂C₆H₅(4-F-benzyl)CONH— 527 a-rr CR⁷ —OCH₂C₆H₅ (4-Cl-benzyl)CONH— 528 a-rr CR⁷—OCH₂C₆H₅ (4-phenoxybenzyl)CONH— 529 a-rr CR⁷ —OCH₂C₆H₅(2-pyridylmethyl)CONH— 530 a-rr CR⁷ —OCH₂C₆H₅ (3-pyridylmethyl)CONH— 531a-rr CR⁷ —OCH₂C₆H₅ (4-pyridylmethyl)CONH— 532 a-rr CR⁷ —OCH₂C₆H₅(cyclopropylethyl)CONH— 533 a-rr CR⁷ —OCH₂C₆H₅ (cyclopropylmethyl)CONH—534 a-rr CR⁷ —OCH₂C₆H₅ (ethyl)NHCONH— 535 a-rr CR⁷ —OCH₂C₆H₅(n-propyl)NHCONH— 536 a-rr CR⁷ —OCH₂C₆H₅ (i-propyl)NHCONH— 537 a-rr CR⁷—OCH₂C₆H₅ (n-butyl)NHCONH— 538 a-rr CR⁷ —OCH₂C₆H₅ (i-butyl)NHCONH— 539a-rr CR⁷ —OCH₂C₆H₅ (t-butyl)NHCONH— 540 a-rr CR⁷ —OCH₂C₆H₅(benzyl)NHCONH— 541 a-rr CR⁷ —OCH₂C₆H₅ (4-Me-benzyl)NHCONH— 542 a-rr CR⁷—OCH₂C₆H₅ (4-MeO-benzyl)NHCONH— 543 a-rr CR⁷ —OCH₂C₆H₅(4-Br-benzyl)NHCONH— 544 a-rr CR⁷ —OCH₂C₆H₅ (4-F-benzyl)NHCONH— 545 a-rrCR⁷ —OCH₂C₆H₅ (4-Cl-benzyl)NHCONH— 546 a-rr CR⁷ —OCH₂C₆H₅(4-phenoxybenzyl)NHCONH— 547 a-rr CR⁷ —OCH₂C₆H₅ (2-pyridylmethyl)NHCONH—548 a-rr CR⁷ —OCH₂C₆H₅ (3-pyridylmethyl)NHCONH— 549 a-rr CR⁷ —OCH₂C₆H₅(4-pyridylmethyl)NHCONH— 550 a-rr CR⁷ —OCH₂C₆H₅(cyclopropylethyl)NHCONH— 551 a-rr CR⁷ —OCH₂C₆H₅(cyclopropylmethyl)NHCONH 552 a-rr N — —H 553 a-rr N — (ethyl)SO₂NH— 554a-rr N — (n-propyl)SO₂NH— 555 a-rr N — (n-butyl)SO₂NH— 556 a-rr N —(phenyl)SO₂NH— 557 a-rr N — (4-Me-phenyl)SO₂NH— 558 a-rr N —(3-Me-phenyl)SO₂NH— 559 a-rr N — (2-Me-phenyl)SO₂NH— 560 a-rr N —(4-Br-phenyl)SO₂NH— 561 a-rr N — (4-Cl-phenyl)SO₂NH— 562 a-rr N —(4-F-phenyl)SO₂NH— 563 a-rr N — (3-Br-phenyl)SO₂NH— 564 a-rr N —(3-Cl-phenyl)SO₂NH— 565 a-rr N — (3-F-phenyl)SO₂NH— 566 a-rr N —(2-Br-phenyl)SO₂NH— 567 a-rr N — (2-Cl-phenyl)SO₂NH— 568 a-rr N —(2-F-phenyl)SO₂NH— 569 a-rr N — (4-F₃C-phenyl)SO₂NH— 570 a-rr N —(3-F₃C-phenyl)SO₂NH— 571 a-rr N — (2-F₃C-phenyl)SO₂NH— 572 a-rr N —(4-MeO-phenyl)SO₂NH— 573 a-rr N — (4-cyano-phenyl)SO₂NH— 574 a-rr N —(4-propyl-phenyl)SO₂NH— 575 a-rr N — (4-i-propyl-phenyl)SO₂NH— 576 a-rrN — (4-butyloxyphenyl)SO₂NH— 577 a-rr N — (benzyl)SO₂NH— 578 a-rr N —(phenylethyl)SO₂NH— 579 a-rr N — (phenylpropyl)SO₂NH— 580 a-rr N —(2-pyridyl)SO₂NH— 581 a-rr N — (3-pyridyl)SO₂NH— 582 a-rr N —(4-pyridyl)SO₂NH— 583 a-rr N — (2-thienyl)SO₂NH— 584 a-rr N —(2,4,6-Me₃-phenyl)SO₂NH— 585 a-rr N — (3,5-Me₂-isoxazolyl)SO₂NH— 586a-rr N — (ethyl)OCONH— 587 a-rr N — (n-propyl)OCONH— 588 a-rr N —(i-propyl)OCONH— 589 a-rr N — (n-butyl)OCONH— 590 a-rr N —(i-butyl)OCONH— 591 a-rr N — (t-butyl)OCONH— 592 a-rr N — (benzyl)OCONH—593 a-rr N — (4-Me-benzyl)OCONH— 594 a-rr N — (4-MeO-benzyl)OCONH— 595a-rr N — (4-Br-benzyl)OCONH— 596 a-rr N — (4-F-benzyl)OCONH— 597 a-rr N— (4-Cl-benzyl)OCONH— 598 a-rr N — (4-phenoxybenzyl)OCONH— 599 a-rr N —(2-pyridylmethyl)OCONH— 600 a-rr N — (3-pyridylmethyl)OCONH— 601 a-rr N— (4-pyridylmethyl)OCONH— 602 a-rr N — (cyclopropylethyl)OCONH— 603 a-rrN — (cyclopropylmethyl)OCONH— 604 a-rr N — (ethyl)CONH— 605 a-rr N —(n-propyl)CONH— 606 a-rr N — (i-propyl)CONH— 607 a-rr N — (n-butyl)CONH—608 a-rr N — (i-butyl)CONH— 609 a-rr N — (t-butyl)CONH— 610 a-rr N —(benzyl)CONH— 611 a-rr N — (4-Me-benzyl)CONH— 612 a-rr N —(4-MeO-benzyl)CONH— 613 a-rr N — (4-Br-benzyl)CONH— 614 a-rr N —(4-F-benzyl)CONH— 615 a-rr N — (4-Cl-benzyl)CONH— 616 a-rr N —(4-phenoxybenzyl)CONH— 617 a-rr N — (2-pyridylmethyl)CONH— 618 a-rr N —(3-pyridylmethyl)CONH— 619 a-rr N — (4-pyridylmethyl)CONH— 620 a-rr N —(cyclopropylethyl)CONH— 621 a-rr N — (cyclopropylmethyl)CONH— 622 a-rr N— (ethyl)NHCONH— 623 a-rr N — (n-propyl)NHCONH— 624 a-rr N —(i-propyl)NHCONH— 625 a-rr N — (n-butyl)NHCONH— 626 a-rr N —(i-butyl)NHCONH— 627 a-rr N — (t-butyl)NHCONH— 628 a-rr N —(benzyl)NHCONH— 629 a-rr N — (4-Me-benzyl)NHCONH— 630 a-rr N —(4-MeO-benzyl)NHCONH— 631 a-rr N — (4-Br-benzyl)NHCONH— 632 a-rr N —(4-F-benzyl)NHCONH— 633 a-rr N — (4-Cl-benzyl)NHCONH— 634 a-rr N —(4-phenoxybenzyl)NHCONH— 635 a-rr N — (2-pyridylmethyl)NHCONH— 636 a-rrN — (3-pyridylmethyl)NHCONH— 637 a-rr N — (4-pyridylmethyl)NHCONH— 638a-rr N — (cyclopropylethyl)NHCONH— 639 a-rr N —(cyclopropylmethyl)NHCONH 640

TABLE 3

R²R^(2b)N— equals a through rr (as defined in Table 2) Ex. #R²R^(2b)N(N)Cphenyl G R⁷ W^(b) m 800 a-rr CR⁷ —H —H 0 801 a-rr CR⁷ —H—CH₃ 0 802 a-rr CR⁷ —H —CH₂(phenyl) 0 803 a-rr CR⁷ —H —CH₂(4-MeO-phenyl)0 804 a-rr CR⁷ —H —CH₂(4-HO-phenyl) 0 805 a-rr CR⁷ —H —CH₂CH(CH₃)₂ 0 806a-rr CR⁷ —H —CH₂CONH(CH₃) 0 807 a-rr CR⁷ —H —CH₂CONH(phenyl) 0 808 a-rrCR⁷ —H —CH₂CONH(benzyl) 0 809 a-rr CR⁷ —H —CH₂NHSO₂(phenyl) 0 810 a-rrCR⁷ —H —CH₂NHSO₂(n-butyl) 0 811 a-rr CR⁷ —H —CH₂NHSO₂(benzyl) 0 812 a-rrCR⁷ —H —CH₂NHCO₂(benzyl) 0 813 a-rr CR⁷ —H —CH₂NHCO₂(n-butyl) 0 814 a-rrCR⁷ —H —CH₂NHCO₂(t-butyl) 0 815 a-rr CR⁷ —H —CH₂NHCO₂(i-butyl) 0 816a-rr CR⁷ —H —CH₂O(benzyl) 0 817 a-rr CR⁷ —H —CH₂(3-indolyl) 0 818 a-rrCR⁷ —OH —H 0 819 a-rr CR⁷ —OH —CH₃ 0 820 a-rr CR⁷ —OH —CH₂(phenyl) 0 821a-rr CR⁷ —OH —CH₂(4-MeO-phenyl) 0 822 a-rr CR⁷ —OH —CH₂(4-HO-phenyl) 0823 a-rr CR⁷ —OH —CH₂CH(CH₃)₂ 0 824 a-rr CR⁷ —OH —CH₂CONH(CH₃) 0 825a-rr CR⁷ —OH —CH₂CONH(phenyl) 0 826 a-rr CR⁷ —OH —CH₂CONH(benzyl) 0 827a-rr CR⁷ —OH —CH₂NHSO₂(phenyl) 0 828 a-rr CR⁷ —OH —CH₂NHSO₂(n-butyl) 0829 a-rr CR⁷ —OH —CH₂NHSO₂(benzyl) 0 830 a-rr CR⁷ —OH —CH₂NHCO₂(benzyl)0 831 a-rr CR⁷ —OH —CH₂NHCO₂(n-butyl) 0 832 a-rr CR⁷ —OH—CH₂NHCO₂(t-butyl) 0 833 a-rr CR⁷ —OH —CH₂NHCO₂(i-butyl) 0 834 a-rr CR⁷—OH —CH₂O(benzyl) 0 835 a-rr CR⁷ —OH —CH₂(3-indolyl) 0 836 a-rr CR⁷—OCH₂CO₂H —H 0 837 a-rr CR⁷ —OCH₂CO₂H —CH₃ 0 838 a-rr CR⁷ —OCH₂CO₂H—CH₂(phenyl) 0 839 a-rr CR⁷ —OCH₂CO₂H —CH₂(4-MeO-phenyl) 0 840 a-rr CR⁷—OCH₂CO₂H —CH₂(4-HO-phenyl) 0 841 a-rr CR⁷ —OCH₂CO₂H —CH₂CH(CH₃)₂ 0 842a-rr CR⁷ —OCH₂CO₂H —CH₂CONH(CH₃) 0 843 a-rr CR⁷ —OCH₂CO₂H—CH₂CONH(phenyl) 0 844 a-rr CR⁷ —OCH₂CO₂H —CH₂CONH(benzyl) 0 845 a-rrCR⁷ —OCH₂CO₂H —CH₂NHSO₂(phenyl) 0 846 a-rr CR⁷ —OCH₂CO₂H—CH₂NHSO₂(n-butyl) 0 847 a-rr CR⁷ —OCH₂CO₂H —CH₂NHSO₂(benzy1) 0 848 a-rrCR⁷ —OCH₂CO₂H —CH₂NHCO₂(benzyl) 0 849 a-rr CR⁷ —OCH₂CO₂H—CH₂NHCO₂(n-butyl) 0 850 a-rr CR⁷ —OCH₂CO₂H —CH₂NHCO₂(t-butyl) 0 851a-rr CR⁷ —OCH₂CO₂H —CH₂NHCO₂(i-butyl) 0 852 a-rr CR⁷ —OCH₂CO₂H—CH₂O(benzyl) 0 853 a-rr CR⁷ —OCH₂CO₂H —CH₂(3-indolyl) 0 854 a-rr CR⁷—OCH₂C₆H₅ —H 0 855 a-rr CR⁷ —OCH₂C₆H₅ —CH₃ 0 856 a-rr CR⁷ —OCH₂C₆H₅—CH₂(phenyl) 0 857 a-rr CR⁷ —OCH₂C₆H₅ —CH₂(4-MeO-phenyl) 0 858 a-rr CR⁷—OCH₂C₆H₅ —CH₂(4-HO-phenyl) 0 859 a-rr CR⁷ —OCH₂C₆H₅ —CH₂CH(CH₃)₂ 0 860a-rr CR⁷ —OCH₂C₆H₅ —CH₂CONH(CH₃) 0 861 a-rr CR⁷ —OCH₂C₆H₅—CH₂CONH(phenyl) 0 862 a-rr CR⁷ —OCH₂C₆H₅ —CH₂CONH(benzyl) 0 863 a-rrCR⁷ —OCH₂C₆H₅ —CH₂NHSO₂(phenyl) 0 864 a-rr CR⁷ —OCH₂C₆H₅—CH₂NHSO₂(n-butyl) 0 865 a-rr CR⁷ —OCH₂C₆H₅ —CH₂NHSO₂(benzyl) 0 866 a-rrCR⁷ —OCH₂C₆H₅ —CH₂NHCO₂(benzyl) 0 867 a-rr CR⁷ —OCH₂C₆H₅—CH₂NHCO₂(n-butyl) 0 868 a-rr CR⁷ —OCH₂C₆H₅ —CH₂NHCO₂(t-butyl) 0 869a-rr CR⁷ —OCH₂C₆H₅ —CH₂NHCO₂(i-butyl) 0 870 a-rr CR⁷ —OCH₂C₆H₅—CH₂O(benzyl) 0 871 a-rr CR⁷ —OCH₂C₆H₅ —CH₂(3-indolyl) 0 872 a-rr N — —H0 873 a-rr N — —CH₃ 0 874 a-rr N — —CH₂(phenyl) 0 875 a-rr N ——CH₂(4-MeO-phenyl) 0 876 a-rr N — —CH₂(4-HO-phenyl) 0 877 a-rr N ——CH₂CH(CH₃)₂ 0 878 a-rr N — —CH₂CONH(CH₃) 0 879 a-rr N ——CH₂CONH(phenyl) 0 880 a-rr N — —CH₂CONH(benzyl) 0 881 a-rr N ——CH₂NHSO₂(phenyl) 0 882 a-rr N — —CH₂NHSO₂(n-butyl) 0 883 a-rr N ——CH₂NHSO₂(benzyl) 0 884 a-rr N — —CH₂NHCO₂(benzyl) 0 885 a-rr N ——CH₂NHCO₂(n-butyl) 0 886 a-rr N — —CH₂NHCO₂(t-butyl) 0 887 a-rr N ——CH₂NHCO₂(i-butyl) 0 888 a-rr N — —CH₂O(benzyl) 0 889 a-rr N ——CH₂(3-indolyl) 0 890 a-rr CR⁷ —H —H 1 891 a-rr CR⁷ —H —CH₃ 1 892 a-rrCR⁷ —H —CH₂(phenyl) 1 893 a-rr CR⁷ —H —CH₂(4-Meo-phenyl) 1 894 a-rr CR⁷—H —CH₂(4-HO-phenyl) 1 895 a-rr CR⁷ —H —CH₂CH(CH₃)₂ 1 896 a-rr CR⁷ —H—CH₂CONH(CH₃) 1 897 a-rr CR⁷ —H —CH₂CONH(phenyl) 1 898 a-rr CR⁷ —H—CH₂CONH(benzyl) 1 899 a-rr CR⁷ —H —CH₂NHSO₂(phenyl) 1 900 a-rr CR⁷ —H—CH₂NHSO₂(n-butyl) 1 901 a-rr CR⁷ —H —CH₂NHSO₂(benzyl) 1 902 a-rr CR⁷ —H—CH₂NHCO₂(benzyl) 1 903 a-rr CR⁷ —H —CH₂NHCO₂(n-butyl) 1 904 a-rr CR⁷ —H—CH₂NHCO₂(t-butyl) 1 905 a-rr CR⁷ —H —CH₂NHCO₂(i-butyl) 1 906 a-rr CR⁷—H —CH₂O(benzyl) 1 907 a-rr CR⁷ —H —CH₂(3-indolyl) 1 908 a-rr CR⁷ —OH —H1 909 a-rr CR⁷ —OH —CH₃ 1 910 a-rr CR⁷ —OH —CH₂(phenyl) 1 911 a-rr CR⁷—OH —CH₂(4-MeO-phenyl) 1 912 a-rr CR⁷ —OH —CH₂(4-HO-phenyl) 1 913 a-rrCR⁷ —OH —CH₂CH(CH₃)₂ 1 914 a-rr CR⁷ —OH —CH₂CONH(CH₃) 1 915 a-rr CR⁷ —OH—CH₂CONH(phenyl) 1 916 a-rr CR⁷ —OH —CH₂CONH(benzyl) 1 917 a-rr CR⁷ —OH—CH₂NHSO₂(phenyl) 1 918 a-rr CR⁷ —OH —CH₂NHSO₂(n-butyl) 1 919 a-rr CR⁷—OH —CH₂NHSO₂(benzyl) 1 920 a-rr CR⁷ —OH —CH₂NHCO₂(benzyl) 1 921 a-rrCR⁷ —OH —CH₂NHCO₂(n-butyl) 1 922 a-rr CR⁷ —OH —CH₂NHCO₂(t-butyl) 1 923a-rr CR⁷ —OH —CH₂NHCO₂(i-butyl) 1 924 a-rr CR⁷ —OH —CH₂O(benzyl) 1 925a-rr CR⁷ —OH —CH₂(3-indolyl) 1 926 a-rr CR⁷ —OCH₂CO₂H —H 1 927 a-rr CR⁷—OCH₂CO₂H —CH₃ 1 928 a-rr CR⁷ —OCH₂CO₂H —CH₂(phenyl) 1 929 a-rr CR⁷—OCH₂CO₂H —CH₂(4-MeO-phenyl) 1 930 a-rr CR⁷ —OCH₂CO₂H —CH₂(4-HO-phenyl)1 931 a-rr CR⁷ —OCH₂CO₂H —CH₂CH(CH₃)₂ 1 932 a-rr CR⁷ —OCH₂CO₂H—CH₂CONH(CH₃) 1 933 a-rr CR⁷ —OCH₂CO₂H —CH₂CONH(phenyl) 1 934 a-rr CR⁷—OCH₂CO₂H —CH₂CONH(benzyl) 1 935 a-rr CR⁷ —OCH₂CO₂H —CH₂NHSO₂(phenyl) 1936 a-rr CR⁷ —OCH₂CO₂H —CH₂NHSO₂(n-butyl) 1 937 a-rr CR⁷ —OCH₂CO₂H—CH₂NHSO₂(benzyl) 1 938 a-rr CR⁷ —OCH₂CO₂H —CH₂NHCO₂(benzyl) 1 939 a-rrCR⁷ —OCH₂CO₂H —CH₂NHCO₂(n-butyl) 1 940 a-rr CR⁷ —OCH₂CO₂H—CH₂NHCO₂(t-butyl) 1 941 a-rr CR⁷ —OCH₂CO₂H —CH₂NHCO₂(i-butyl) 1 942a-rr CR⁷ —OCH₂CO₂H —CH₂O(benzyl) 1 943 a-rr CR⁷ —OCH₂CO₂H—CH₂(3-indolyl) 1 944 a-rr CR⁷ —OCH₂C₆H₅ —H 1 945 a-rr CR⁷ —OCH₂C₆H₅—CH₃ 1 946 a-rr CR⁷ —OCH₂C₆H₅ —CH₂(phenyl) 1 947 a-rr CR⁷ —OCH₂C₆H₅—CH₂(4-MeO-phenyl) 1 948 a-rr CR⁷ —OCH₂C₆H₅ —CH₂(4-HO-phenyl) 1 949 a-rrCR⁷ —OCH₂C₆H₅ —CH₂CH(CH₃)₂ 1 950 a-rr CR⁷ —OCH₂C₆H₅ —CH₂CONH(CH₃) 1 951a-rr CR⁷ —OCH₂C₆H₅ —CH₂CONH(phenyl) 1 952 a-rr CR⁷ —OCH₂C₆H₅—CH₂CONH(benzyl) 1 953 a-rr CR⁷ —OCH₂C₆H₅ —CH₂NHSO₂(phenyl) 1 954 a-rrCR⁷ —OCH₂C₆H₅ —CH₂NHSO₂(n-butyl) 1 955 a-rr CR⁷ —OCH₂C₆H₅—CH₂NHSO₂(benzyl) 1 956 a-rr CR⁷ —OCH₂C₆H₅ —CH₂NHCO₂(benzyl) 1 957 a-rrCR⁷ —OCH₂C₆H₅ —CH₂NHCO₂(n-butyl) 1 958 a-rr CR⁷ —OCH₂C₆H₅—CH₂NHCO₂(t-butyl) 1 959 a-rr CR⁷ —OCH₂C₆H₅ —CH₂NHCO₂(i-butyl) 1 960a-rr CR⁷ —OCH₂C₆H₅ —CH₂O(benzyl) 1 961 a-rr CR⁷ —OCH₂C₆H₅—CH₂(3-indolyl) 1 962 a-rr N — —H 1 963 a-rr N — —CH₃ 1 964 a-rr N ——CH₂(phenyl) 1 965 a-rr N — —CH₂(4-MeO-phenyl) 1 966 a-rr N ——CH₂(4-HO-phenyl) 1 967 a-rr N — —CH₂CH(CH₃)₂ 1 968 a-rr N ——CH₂CONH(CH₃) 1 969 a-rr N — —CH₂CONH(phenyl) 1 970 a-rr N ——CH₂CONH(benzyl) 1 971 a-rr N — —CH₂NHSO₂(phenyl) 1 972 a-rr N ——CH₂NHSO₂(n-butyl) 1 973 a-rr N — —CH₂NHSO₂(benzyl) 1 974 a-rr N ——CH₂NHCO₂(benzyl) 1 975 a-rr N — —CH₂NHCO₂(n-butyl) 1 976 a-rr N ——CH₂NHCO₂(t-butyl) 1 977 a-rr N — —CH₂NHCO₂(i-butyl) 1 978 a-rr N ——CH₂O(benzyl) 1 979 a-rr N — —CH₂(3-indolyl) 1 980

Utility

The compounds of this invention possess antiplatelet efficacy, asevidenced by their activity in standard platelet aggregation assays orplatelet fibrinogen binding assays, as described below. A compound isconsidered to be active in these assays if it has an IC₅o value of lessthan about 50 μM. It is more preferred that a compound has an IC₅₀ valueof less than about 1 μM. It is even more preferred that a compound hasan IC₅₀ value of less than about 0.1 μM.

Representative compounds of the invention have been shown to have IC₅₀values of less than about 50 μM. Platelet aggregation and fibrinogenbinding assays which may be used to demonstrate the antiplateletactivity of the compounds of the invention are described below.

Platelet Aggregation Assay:

Venous blood was obtained from the arm of a healthy human donor who wasdrug-free and aspirin-free for at least two weeks prior to bloodcollection. Blood was collected into 10 mL citrated Vacutainer tubes.The blood was centrifuged for 15 minutes at 150×g at room temperature,and platelet-rich plasma (PRP) was removed. The remaining blood wascentrifuged for 15 minutes at 1500×g at room temperature, andplatelet-poor plasma (PPP) was removed. Samples were assayed on aaggregometer (PAP-4 Platelet Aggregation Profiler), using PPP as theblank (100% transmittance). 200 luL of PRP was added to each micro testtube, and transmittance was set to 0%. 20 μL of various agonists (ADP,collagen, arachidonate, epinephrine, thrombin) were added to each tube,and the aggregation profiles were plotted (% transmittance versus time).The results are expressed as % inhibition of agonist-induced plateletaggregation. For the IC₅₀ evaluation, the test compounds were added atvarious concentrations prior to the activation of the platelets. Esterprodrugs were preincubated (10⁻³ M F.C.) with 100 IU/mL Porcine liveresterase (Sigma Chemical Co., St. Louis, Mo., #E-3128) for 2 hours at37° C. Aliquots are then diluted in 0.1 M Tris, pH 7.4, to the desiredconcentrations. Aliquots of 20 μl of the esterase pretreated prodrugsare added to 200 μl of human platelet rich plasma. Samples were placedin platelet profiler (aggregometer) for 8 minutes at 37° C., followed bythe addition of 100 μM Adenosine Diphosphate, (Sigma Chemical Co., St.Louis, Mo., #A-6521), to induce platelet aggregation. Plateletaggregation was allowed to proceed for 5 minutes. Percent inhibition iscalculated using percent aggregation in the presence of the testcompound divided by percent aggregation of control, times 100. Thisvalue is subtracted from 100, yielding percent inhibition. Calculationof IC₅₀ is performed on a Texas Instruments TI59 with an IC₅₀ program.

Purified GPIIb/IIIa-Fibrinogen BindinQ ELISA

The following reagents are used in the GPIIb/IIIa-fibrinogen bindingELISA:

purified GPIIb/IIIa (148.8 μg/mL);

biotinylated fibrinogen (˜1 mg/mL or 3000 nM);

anti-biotin alkaline phosphatase conjugate (Sigma no. A7418);

flat-bottom, high binding, 96-well plates (Costar Cat. no. 3590);

phosphatase substrate (Sigma 104) (40 mg capsules);

bovine serum albumin (BSA) (Sigma no. A3294);

Alkaline Phosphatase buffer −0.1 M glycine-HCl, 1 mM MgCl₂.6H₂O, 1 mMZnCl₂, pH 10.4;

Binding buffer −20 mM Tris-HCl, 150 mM NaCl, 1 mM CaCl₂.2H₂O, 0.02%NaN₃, pH 7.0;

Buffer A −50 mM Tris-HCl, 100 mM NaCl, 2 mM CaCl₂.2H₂O, 0.02% NaN₃, pH7.4;

Buffer A +3.5% BSA (Blocking buffer);

Buffer A +0.1% BSA (Dilution buffer);

2N NaOH.

The following method steps are used in the GPIIb/IIIa-fibrinogen bindingELISA:

Coat plates with GPIIb/IIIa in Binding buffer (125 ng/100 μL/well)overnight at 4° C. (Leave first column uncoated for non-specificbinding). Cover and freeze plates at −70° C. until used. Thaw plate 1hour at room temperature or overnight at 4° C. Discard coating solutionand wash once with 200 μL Binding buffer per well. Block plate 2 hoursat room temperature on shaker with 200 μL Buffer A +3.5% BSA (Blockingbuffer) per well. Discard Blocking buffer and wash once with 200 μLBuffer A +0.1% BSA (Dilution buffer) per well. Pipet 11 μL of testcompound (10× the concentration to be tested in Dilution buffer) intoduplicate wells. Pipet 11 μL Dilution buffer into non-specific and totalbinding wells. Add 100 μL Biotinylated fibrinogen ({fraction (1/133)} inDilution buffer, final concentration=20 nM) to each well. Incubateplates for 3 hours at room temperature on a plate shaker. Discard assaysolution and wash twice with 300 μL Binding buffer per well. Add 100 μLAnti-biotin alkaline phosphatase conjugate ({fraction (1/1500)} inDilution buffer) to each well. Incubate plates for 1 hour at roomtemperature on plate shaker. Discard conjugate and wash twice with 30051 Binding buffer per well. Add 100 uL Phosphatase substrate (1.5 mg/mLin Alkaline phosphatase buffer) to each well. Incubate plate at roomtemperature on shaker until color develops. Stop color development byadding 25 μL 2N NaOH per well. Read plate at 405 nm. Blank againstnon-specific binding (NSB) well. % Inhibition is calculated as follows:

% Inhibition=100−((Test Compound Abs/Total Abs)×100).

Platelet-Fibrinogen Binding Assay:

Binding of ¹²⁵I-fibrinogen to platelets was performed as described byBennett et al. (1983) Proc. Natl. Acad. Sci. USA 80: 2417-2422, withsome modifications as described below. Human PRP (h-PRP) was applied toa Sepharose column for the purification of platelet fractions. Aliquotsof platelets (5×10⁸ cells) along with 1 mM calcium chloride were addedto removable 96 well plates prior to the activation of the human gelpurified platelets (h-GPP). Activation of the human gel purifiedplatelets was achieved using ADP, collagen, arachidonate, epinephrine,and/or thrombin in the presence of the ligand, ¹²⁵I-fibrinogen. The¹²⁵I-fibrinogen bound to the activated platelets was separated from thefree form by centrifugation and then counted on a gamma counter. For anIC₅₀ evaluation, the test compounds were added at various concentrationsprior to the activation of the platelets.

The compounds of Formula (I) of the present invention may also possessthrombolytic efficacy, that is, they are capable of lysing (breaking up)already formed platelet-rich fibrin blood clots, and thus are useful intreating a thrombus formation, as evidenced by their activity in thetests described below. Preferred compounds of the present invention foruse in thrombolysis include those compounds having an IC₅₀ value (thatis, the molar concentration of the compound capable of achieving 50%clot lysis) of less than about 1 μM, more preferably an IC₅₀ value ofless than about 0.1 μM.

Thrombolytic Assay:

Venous blood was obtained from the arm of a healthy human donor who wasdrug-free and aspirin free for at least two weeks prior to bloodcollection, and placed into 10 ml citrated Vacutainer tubes. The bloodwas centrifuged for 15 minutes at 1500×g at room temperature, andplatelet rich plasma (PRP) was removed. To the PRP was then added 1×10⁻³M of the agonist ADP, epinephrine, collagen, arachidonate, serotonin orthrombin, or a mixture thereof, and the PRP incubated for 30 minutes.The PRP was centrifuged for 12 minutes at 2500×g at room temperature.The supernatant was then poured off, and the platelets remaining in thetest tube were resuspended in platelet poor plasma (PPP), which servedas a plasminogen source. The suspension was then assayed on a CoulterCounter (Coulter Electronics, Inc., Hialeah, Fla.), to determine theplatelet count at the zero time point. After obtaining the zero timepoint, test compounds were added at various concentrations. Test sampleswere taken at various time points and the platelets were counted usingthe Coulter Counter. To determine the percent of lysis, the plateletcount at a time point subsequent to the addition of the test compoundwas subtracted from the platelet count at the zero time point, and theresulting number divided by the platelet count at the zero time point.Multiplying this result by 100 yielded the percentage of clot lysisachieved by the test compound. For the IC₅₀ evaluation, the testcompounds were added at various concentrations, and the percentage oflysis caused by the test compounds was calculated.

The compounds of Formula (I) of the present invention are also usefulfor administration in combination with anti-coagulant agents such aswarfarin or heparin, or anti-platelet agents such as aspirin, piroxicamor ticlopidine, or thrombin inhibitors such as boropeptides, hirudin orargatroban, or thrombolytic agents such as tissue plasminogen activator,anistreplase, urokinase, streptokinase, or reteplase or combinationsthereof.

The compounds of Formula (I) of the present invention may also be usefulas antagonists of other integrins such as for example, the α_(v)/β₃ orvitronectin receptor, α₄/β₁ or α₅/β₁ and as such may also have utilityin the treatment and diagnosis of osteoporosis, cancer metastasis,diabetic retinopathy, rheumatoid arthritis, inflammation, and autoimmunedisorders. The compounds of Formula (I) of the present invention may beuseful for the treatment or prevention of other diseases which involvecell adhesion processes, including, but not limited to, infammation,bone degradation, rheumatoid arthritis, asthma, allergies, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease and otherautoimmune diseases.

The compounds of the present invention may be useful for the treatmentor prevention of other diseases which involve cell adhesion processes,including, but not limited to, inflammation, bone degradation,thrombosis, rheumatoid arthritis, asthma, allergies, adult respiratorydistress syndrome, graft versus host disease, organ transplantation,septic shock, psoriasis, eczema, contact dermatitis, osteoarthritis,atherosclerosis, metastasis, wound healing, diabetic retinopathy,inflammatory bowel disease and other angiogenic disorders.

The integrin antagonist activity of the compounds of the presentinvention is demonstrated using assays which measure the binding of aspecific integrin to a native ligand, for example, using the ELISA assaydescribed below for the binding of vitronectin to the α_(v)/β₃ receptor.The compounds provided by this invention are also useful as standardsand reagents in determining the ability of a potential pharmaceutical toinhibit integrin-ligand binding. These would be provided in commercialkits comprising a compound of this invention.

Integrin Cell-Based Adhesion Assays

In the adhesion assays, a 96 well plate was coated with the ligand(i.e., fibrinogen) and incubated overnight at 40 C. The following day,the cells were harvested, washed and loaded with a fluorescent dye.Compounds and cells were added together and then were immediately addedto the coated plate. After incubation, loose cells are removed from theplate, and the plate (with adherent cells) is counted on a fluorometer.The ability of test compounds to inhibit cell adhesion by 50% is givenby the IC₅₀ value and represents a measure of potency of inhibition ofintegrin mediated binding. Compounds were tested for their ability toblock cell adhesion using assays specific for α_(v)/β₃, α_(v)/β₅ andα₅/β₁ integrin interactions.

Dosage and Formulation

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixirs, tinctures, suspensions, syrups, and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous, or intramuscular form, all using dosageforms well known to those of ordinary skill in the pharmaceutical arts.An effective but non-toxic amount of the compound desired can beemployed as an anti-aggregation agent. Finally, the compounds of theinvention may also be administered intranasally.

The compounds of this invention can be administered by any means thatproduces contact of the active agent with the agent's site of action,glycoprotein IIb/IIIa (GPIIb/IIIa), in the body of a mammal. They can beadministered by any conventional means available for use in conjunctionwith pharmaceuticals, either as individual therapeutic agents or in acombination of therapeutic agents, such as a second antiplatelet agentsuch as aspirin or ticlopidine which are agonist-specific. They can beadministered alone, but generally administered with a pharmaceuticalcarrier selected on the basis of the chosen route of administration andstandard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. An ordinarily skilled physician or veterinarian canreadily determine and prescribe the effective amount of the drugrequired to prevent, counter, or arrest the progress of the condition.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about1.0 to 20 g/kg/day. Intravenously, the most preferred doses will angefrom about 1 to about 10 mg/kg/minute during a onstant rate infusion.Advantageously, compounds of the resent invention may be administered ina single daily ose, or the total daily dosage may be administered individed doses of two, three, or four times daily.

The compounds for the present invention can be administered inintranasal form via topical use of suitable intranasal vehicles, or viatransdermal routes, using those forms of transdermal skin patches wallknown to those of ordinary skill in that art. To be administered in theform of a transdermal delivery system, the dosage administration will,of course, be continuous rather than intermittant throughout the dosageregimen.

The active ingredient can be administered intranasally to a mammal at adosage range of about 0.01 to 0.5 mg/kg while the preferred dosage rangeis about 0.01-0.1 mg/kg.

Compositions of the active ingredients can be administered intranasallyby preparing a suitable formulation of the active ingredient byprocedures well known to those skilled in the art. Preferably theformulations are prepared with suitable nontoxic pharmaceuticallyacceptable ingredients. These ingredients are known to those skilled inthe preparation of nasal dosage forms and some of these can be found inREMINGTON'S PHARMACEUTICAL SCIENCES. 17th edition, 1985 a standardreference in the field. The choice of suitable carriers is highlydependent upon the exact nature of the nasal dosage form desired, e.g.,solutions, suspensions, ointments, or gels. Nasal dosage forms generallycontain large amounts of water in addition to the active ingredient.Minor amounts of other ingredients such as pH adjusters, emulsifiers ordispersing agents, preservatives, surfactants, jelling agents, orbuffering and other stabilizing and solubilizing agents may also bepresent. Preferably, the nasal dosage form should be isotonic with nasalsecretions.

The nasal formulation can be administered as drops, sprays, aerosols orby any other intranasal dosage form. ptionally, the delivery system canbe a unit dose delivery ystem. The volume of solution or suspensiondelivered per ose can be anywhere from 5 to 400 luL, and preferablyetween 50 and 150 pL. Delivery systems for these various osage forms canbe dropper bottles, plastic squeeze units, tomizers, nebulizers orpharmaceutical aerosols in either nit dose or multiple dose packages.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients, orcarriers (collectively referred to herein as carrier materials) suitablyselected with respect to the intended form of administration, that is,oral tablets, capsules, elixirs, syrups and the like, and consistentwith conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administerediontophoretic delivery systems, also refered to as electrotransportsystems, by one skilled in the art of iontophoretic delivery.Controlled, continuous delivery of drugs at constant rates is a highlyuseful method of delivering medications. This kind of delivery ensuresrelatively constant plasma concentrations and, more importantly, propercontrol of pharmacologic and toxic drug effect. Transdermal delivery canbe an especially useful means of controlled, continuous delivery ofdrugs that exhibit no/low oral bioavailability while avoiding theinconvenience and discomfort of administration by injection. Thecompounds of the present invention can also be administered in the formof liposome delivery systems, such as small unilamellar vesicles, largeunilamallar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 100 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.5-95% by weight based on the total weight of the composition.

The active ingredient can be administered orally in solid dosage forms,such as capsules, tablets, and powders, or in liquid dosage forms, suchas elixirs, syrups, and suspensions. It can also be administeredparenterally, in sterile liquid dosage forms.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Representative useful pharmaceutical dosage-forms for administration ofthe compounds of this invention can be illustrated as follows:

Capsules

A large number of unit capsules are prepared by filling standardtwo-piece hard gelatin capsules each with 1-20 milligrams of powderedactive ingredient, 150 milligrams of lactose, 50 milligrams ofcellulose, and 6 milligrams magnesium stearate.

Soft Gelatin Capsules

A mixture of active ingredient in a digestable oil such as soybean oil,cottonseed oil or olive oil is prepared and injected by means of apositive displacement pump into gelatin to form soft gelatin capsulescontaining 1-20 milligrams of the active ingredient. The capsules arewashed and dried.

Tablets

A large number of tablets are prepared by conventional procedures sothat the dosage unit was 1-20 milligrams of active ingredient, 0.2milligrams of colloidal silicon dioxide, 5 milligrams of magnesiumstearate, 275 milligrams of microcrystalline cellulose, 11 milligrams ofstarch and 98.8 milligrams of lactose. Appropriate coatings may beapplied to increase palatability or delay absorption.

Injectable

A parenteral composition suitable for administration by injection isprepared by stirring 1.5% by weight of active ingredient in 10% byvolume propylene glycol and water. The solution is made isotonic withsodium chloride and sterilized.

Suspension

An aqueous suspension is prepared for oral administration so that each 5mL contain 1-20 mg of finely divided active ingredient, 200 mg of sodiumcarboxymethyl cellulose, 5 mg of sodium benzoate, 1.0 g of sorbitolsolution, U.S.P., and 0.025 mL of vanillin.

The compounds of the present invention may be administered incombination with a second therapeutic agent selected from: ananti-coagulant agent such as warfarin, heparin, or low molecular weightheparin; an anti-platelet agent such as aspirin, piroxicam orticlopidine; a thrombin inhibitor such as a boropeptide thrombininhibitor, hirudin, or Factor Xa inhibitor; or a thrombolytic agent suchas plasminogen activators, such as tissue plasminogen activator,anistreplase, urokinase, streptokinase, or reteplase. The compound ofFormula (I) and such second therapeutic agent can be administeredseparately or as a physical combination in a single dosage unit, in anydosage form and by various routes of administration, as described above.

The compound of Formula (I) may be formulated together with the secondtherapeutic agent in a single dosage unit (that is, combined together inone capsule, tablet, powder, or liquid, etc.). When the compound ofFormula (I) and the second therapeutic agent are not formulated togetherin a single dosage unit, the compound of Formula (I) and the secondtherapeutic agent (anti-coagulant agent, anti-platelet agent, thrombininhibitor, and/or thrombolytic agent) may be administered essentially atthe same time, or in any order; for example the compound of Formula (I)may be administered first, followed by administration of the secondagent (anti-coagulant agent, anti-platelet agent, thrombin inhibitor,and/or thrombolytic agent). When not administered at the same time,preferably the administration of the compound of Formula (I) and thesecond therapeutic agent occurs less than about one hour apart.

A preferable route of administration of the compound of Formula (I) isoral. Although it is preferable that the compound of Formula (I) and thesecond therapeutic agent (anti-coagulant agent, anti-platelet agent,thrombin inhibitor, and/or thrombolytic agent) are both administered bythe same route (that is, for example, both orally), if desired, they mayeach be administered by different routes and in different dosage forms(that is, for example, one component of the combination product may beadministered orally, and another component may be administeredintravenously).

The dosage of the compound of Formula (I) when administered alone or incombination with a second therapeutic agent may vary depending uponvarious factors such as the pharmacodynamic characteristics of theparticular agent and its mode and route of administration, the age,health and weight of the recipient, the nature and extent of thesymptoms, the kind of concurrent treatment, the frequency of treatment,and the effect desired, as described above.

Although the proper dosage of the compound of Formula (I) whenadministered in combination with the second therapeutic agent will bereadily ascertainable by a medical practitioner skilled in the art, oncearmed with the present disclosure, by way of general guidance, where thecompounds of this invention are combined with anti-coagulant agents, forexample, a daily dosage may be about 0.1 to 100 milligrams of thecompound of Formula (I) and about 1 to 7.5 milligrams of theanticoagulant, per kilogram of patient body weight. For a tablet dosageform, the novel compounds of this invention generally may be present inan amount of about 1 to 10 milligrams per dosage unit, and theanti-coagulant in an amount of about 1 to 5 milligrams per dosage unit.

Where the compounds of Formula (I) are administered in combination witha second anti-platelet agent, by way of general guidance, typically adaily dosage may be about 0.01 to 25 milligrams of the compound ofFormula (I) and about 50 to 150 milligrams of the additionalanti-platelet agent, preferably about 0.1 to 1 milligrams of thecompound of Formula (I) and about 1 to 3 milligrams of antiplateletagents, per kilogram of patient body weight.

Further, by way of general guidance, where the compounds of Formula (I)are adminstered in combination with thrombolytic agent, typically adaily dosage may be about 0.1 to 1 milligrams of the compound of FormulaI, per kilogram of patient body weight and, in the case of thethrombolytic agents, the usual dosage of the thrombolyic agent whenadministered alone may be reduced by about 70-80% when administered witha compound of Formula I.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of Formula I, generally the amount ofeach component in a typical daily dosage and typical dosage form may bereduced relative to the usual dosage of the agent when administeredalone, in view of the additive or synergistic effect of the therapeuticagents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of Formula (I) and a second therapeuticagent are combined in a single dosage unit they are formulated such thatalthough the active ingredients are combined in a single dosage unit,the physical contact between the active ingredients is minimized (thatis, reduced). For example, one active ingredient may be enteric coated.By enteric coating one of the active ingredients, it is possible notonly to minimize the contact between the combined active ingredients,but also, it is possible to control the release of one of thesecomponents in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with asustained-release material which effects a sustained-release throughoutthe gastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low-viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

The present invention also includes pharmaceutical kits useful, forexample, in the inhibition of platelet aggregation, the treatment ofblood clots, and/or the treatment of thromboembolic disorders, whichcomprise one or more containers containing a pharmaceutical compositioncomprising a therapeutically effective amount of a compound of FormulaI. Such kits may further include, if desired, one or more of variousconventional pharmaceutical kit components, such as, for example,containers with one or more pharmaceutically acceptable carriers,additional containers, etc., as will be readily apparent to thoseskilled in the art. Instructions, either as inserts or as labels,indicating quantities of the components to be administered, guidelinesfor administration, and/or guidelines for mixing the components, mayalso be included in the kit.

In the present disclosure it should be understood that the specifiedmaterials and conditions are important in practicing the invention butthat unspecified materials and conditions are not excluded so long asthey do not prevent the benefits of the invention from being realized.

What is claimed is:
 1. A compound of Formula (I):

or a pharmaceutically acceptable salt form thereof wherein: b is asingle or double bond; R¹ is selected from R^(2a)(R³)N—V—,R²(R^(2b))N(R³N═)C—V—, R²(R^(2b))N(R³N═)CNH—V—, R²(R¹¹O)N(R³N═)C—V—,R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from: -(C₁-C₄ alkyl)-, -(C₂-C₄ alkenyl)-, -(C₂-C₄alkynyl)-, -(phenyl)-, said phenyl substituted with 0-2 groupsindependently selected from R⁹, -(pyridyl)-, said pyridyl substitutedwith 0-2 groups independently selected from R⁹, or -(pyridazinyl)-, saidpyridazinyl substituted with 0-2 groups independently selected from R⁹;Z is selected from: a bond, O, S, S(═O), and S(═O)₂; R^(2a) is R² orR²(R^(2b))N(R³N═)C—; R², R^(2b), and R³ are independently selected from:H, C₁-C₁₀ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl, aryl,arylcarbonyl, aryl(C₁-C₄ alkyl)-, diarylmethyl, 2,2-diarylethyl,benzhydryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₅ alkyl)-, and acleavable protecting group selected from: C₁-C₆ alkoxycarbonyl, C₃-C₁₁cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C₁-C₁₀ alkoxy) carbonyl, (C₁-C₆ alkyl)carbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and (C₃-C₁₁cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl, wherein at least one ofR², R^(2b), and R³ is H or a cleavable protecting group; wherein saidaryl groups of R², R^(2b), and R³ may be substituted with 0-3 groupsselected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, —CN,—SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —SO₂NH₂, —NR²¹R²², C₁-C₄ haloalkyl,methylenedioxydiyl, and ethylenedioxydiyl; and  said heteroaryl groupsof R², R^(2b), and R³ may be substituted with 0-2 groups selected fromhydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, SO₂CH₃, and —NR²¹R²²;alternatively, R² and R^(2b) can be taken together with the nitrogenatom to which they are attached to form a 5-14 membered heterocyclicring optionally containing one additional heteroatom selected from: N,O, or S; said heterocyclic ring being monocyclic, bicyclic, ortricyclic; said heterocyclic ring being substituted with 0-3 R⁴; R⁴,when a substituent on carbon, is independently selected from H, C₁-C₄alkyl, aryl, aryl(C₁-C₆ alkyl)-, C₁-C₄ alkoxy, halogen,methylenedioxydiyl, (C₁-C₆ alkyl)SO₂NH—, (C₆-C₁₁ aryl) SO₂NH—, (C₁-C₆alkyl)CONH—, (C₆-C₁₁ aryl)CONH—, (C₁-C₆ alkyl)NHCO—, (C₆-C₁₁ aryl)NHCO—,(C₁-C₆ alkyl)NHCO—, (C₆-C₁₁ aryl)NHCO—, (C₁-C₆ alkyl)NHSO₂—, (C₆-C₁₁aryl)NHSO₂—, (C₁-C₆ alkyl)SO₂—, (C₆-C₁₁ aryl)SO₂—, wherein said arylgroups may be optionally substituted with 0-3 groups selected fromhydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, OCF₃, SCH₃, S(O)CH₃,SO₂CH₃, —NR²¹R²², C₁-C₄ haloalkyl, methylenedioxydiyl, andethylenedioxydiyl; alternatively, when two R⁴ groups are attached toadjacent carbon atoms, they may be taken together with the atoms towhich they are attached to form a fused 5-7 membered saturated,unsaturated or aromatic carbocyclic ring; alternatively, when R⁴ isattached to a saturated carbon atom, it may also be ═O or ═S; R⁴, when asubstituent on nitrogen, is independently selected from: H, C₁-C₆ alkyl,C₃-C₆ alkenyl, C₁-C₁₀ alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀alkylsulfonyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-,C₃-C₁₁ cycloalkoxycarbonyl, C₇-Cil bicycloalkoxycarbonyl, aryl,aryl(C₁-C₁₀ alkyl)-, diarylmethyl, 2,2-diarylethyl, benzhydryl(C₁-C₄alkyl)-, arylcarbonyl, aryloxycarbonyl, arylsulfonyl, aryl(C₁-C₁₀alkyl)sulfonyl, aryl(C₂-C₁₀ alkenyl)sulfonyl, aryl(C₁-C₁₀alkoxy)carbonyl, heteroaryl, heteroarylsulfonyl, heteroarylcarbonyl,heteroaryl (C₁-C₁₀ alkyl) -, and heteroaryl(C₁-C₁₀ alkyl)carbonyl,wherein said aryl or heteroaryl groups may be additionally substitututedwith 0-2 groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, SCH₃, SOCH₃, SO₂CH₃, or —NR²¹R²²; R⁴, when a substituent onsulfur, may be ═O; G is or N; X is —CH₂—CH(W^(a))—, —CH(W^(b))—CH₂— or—CH(W^(b))—; Y is selected from hydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁cycloalkyloxy, C₆-C₁₀ aryloxy, C₇-C₁₁ arylalkyloxy, C₂-C₁₀alkylcarbonyloxyalkyloxy, C₂-C₁₁ alkoxycarbonyloxyalkyloxy, C₂-C₁₁alkoxycarbonylalkyloxy, C₄-C₁₁ cycloalkylcarbonyloxyalkyloxy, C₄-C₁₁cycloalkoxycarbonyloxyalkyloxy, C₄-C₁₁ cycloalkoxycarbonylalkyloxy,C₇-C₁₁ aryloxycarbonylalkyloxy, C₇-C₁₂ aryloxycarbonyloxyalkyloxy,C₇-C₁₂ arylcarbonyloxyalkyloxy, C₄-C₁₀ alkoxyalkylcarbonyloxyalkyloxy,(5-(C₁-C₄ alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R²⁸)(R²⁹)N-(C₁-C₁₀ alkoxy)-; W^(a) is selected from: H, hydroxy, —NR¹⁶R²⁰,—NR²⁵R²⁶, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl substituted with 0-3 R⁸, and arylsubstituted with 0-3 R⁸; W^(b) is selected from: H, CH₂OH, CH₂OR¹²,CH₂CO₂R¹², CH₂C(═O)NHR¹⁸, CH₂NR¹⁶R²⁰, CH₂NR²⁵R²⁶, C₃-C₆ alkenyl, C₃-C₁₀cycloalkyl, C₄-C₁₁ cycloalkylmethyl, C₁-C₈ alkyl substituted with 0-2R⁸, aryl substituted with 0-3 R⁸, and aryl(C₁-C₆ alkyl), said arylsubstituted with 0-3 R⁸; R⁵ is selected from: H, hydroxy, fluoro,—NH(CH₂)_(s)R⁸, —NH(CH₂)_(s)CO₂R¹², —O(CH₂)_(s)CO₂R¹², —NR²⁵R²⁶, C₁-C₈alkyl substituted with 0-2 R⁸, C₁-C₁₀ alkoxy substituted with 0-2 R⁸,C₃-C₆ alkenyl, C₄-Cil cycloalkylmethyl, and aryl(C₁-C₆ alkyl)-; R⁶ is H,methyl, or fluoro; alternatively, R⁵ and R⁶ can be taken together to be═O, ═CHR^(8a) or ═CHCH₂R⁸; R⁷ is selected from: H, hydroxy, —OR¹²,—OC(═O)R¹³, —OC(═O)OR¹⁴, —OC(═O)NR²³R²⁴, and —O(CH₂)_(s)CO₂R¹²;alternatively, when G is C(R⁷), R⁷ and R⁶ may be taken together to forma carbon-carbon double bond; R^(7a) and R^(7b) are independentlyselected from H, methyl, ethyl, and ═O; alternatively, when R⁷ andR^(7a) occur on adjacent carbons R⁷ and R^(7a) may be taken together toform a carbon-carbon double bond; alternatively, when R^(7a) and R^(7b)occur on adjacent carbons R^(7a) and R^(7b) may be taken together toform a six carbon aromatic ring; R⁸ is selected from: H, hydroxy, cyano,—CO₂R¹², —C(═O)R¹³, —OC(═O)R¹³, —OC(═O)OR¹⁴, —OR¹², —OCH₂CO₂R¹²,—CO₂CH₂CO₂R¹², —OC(═O)NR²³R²⁴, —C(═O)NR²³R²⁴, —NR²⁵R²⁶, —NR²⁷C(═O)R¹³,—NR²⁷C (═O) OR¹⁴, —NR²⁷SO₂R¹⁴, —SR¹⁴, —SOR¹⁴, —SO₂R¹⁴, —SO₂NR²³R²⁴,C₁-C₁₀ alkoxy, C₁-C₁₀ alkylcarbonyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl,C₄-C₁₁ cycloalkylmethyl, aryl, wherein said aryl is substituted with 0-3groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹²,SO₂Me, SOMe, SMe and —NMe₂, aryl(C₁-C₄ alkyl)-, wherein said aryl issubstituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, CO₂R¹², SO₂Me, SOMe, SMe, and —NMe₂, and a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe and —NMe₂; R^(8a) is selected from: H, cyano, —CO₂R¹²,—C(═O)R¹³, —C(═O)NR²³R²⁴, C₁-C₁₀ alkylcarbonyl, C₂-C₆ alkenyl, C₃-C₁₀cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl, wherein said aryl issubstituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, CO₂R¹², SO₂Me, SOMe, SMe and —NMe₂, and aryl(C₁-C₄ alkyl)-,wherein said aryl is substituted with 0-3 groups selected from halogen,C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me, SOMe, SMe, and —NMe₂; R⁹is selected from H, halogen, CF₃, CN, C₁-C₄ alkyl, and C₁-C₄ alkoxy; R¹⁰is selected from: H, hydroxy, CN, carboxy, —NR²⁵R²⁶; C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₇-C₁₄ bicycloalkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aryl, piperidinyl, morpholinyl, andpyridinyl; R¹¹ is selected from: H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, andC₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R¹² is selected from: H, C₁-C₈alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R¹³ isselected from: hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹¹; R¹⁴is selected from: C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substitutedwith 1-2 R¹⁰; R¹⁵ is selected from: H, OH, —OR¹², —CO₂R¹²,—C(═O)NR²³R²⁴, —OC(═O)NR²³R²⁴, C₁-C₁₀ alkoxycarbonyl substituted with0-2 R⁸; C₁-C₁₀ alkyl substituted with 0-3 R⁸; C₂-C₁₀ alkenyl substitutedwith 0-3 R⁸; and C₁-C₁₀ alkoxy substituted with 0-3 R⁸; R¹⁶ is selectedfrom: —C(═O)OR¹⁷, —C(═O)R¹⁸, —C(═O)NR¹⁷R¹⁸, —C(═O)NHSO₂R¹⁷, —C(═O)NHC(═O)R¹⁷, —C(═O)NHC(═O)OR¹⁷, —C(═O)NHSO₂NHR¹⁷, —O₂R¹⁷—SO₂NR¹⁷R¹⁸,and —SO₂NHC(═O)OR¹⁷; R¹⁷ is selected from: C₁-C₈ alkyl substituted with0-2 R¹⁹, C₃-C₈ alkenyl substituted with 0-2 R¹⁹, C₃-C₈ alkynylsubstituted with 0-2 R¹⁹, C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹,aryl substituted with 0-4 R¹⁹, aryl (C₁-C₆ alkyl)- substituted with 0-4R¹⁹, a 5-10 membered heterocyclic ring system having 1-3 heteroatomsselected independently from O, S, and N, said heterocyclic ring beingsubstituted with 0-4 R¹⁹, and C₁-C₆ alkyl substituted with a 5-10membered heterocyclic ring system having 1-3 heteroatoms selectedindependently from O, S, and N, said heterocyclic ring being substitutedwith 0-4 R¹⁹; R¹⁸ is selected from H and R¹⁷; R¹⁹ is selected from: H,halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl; R²⁰ isselected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁cycloalkyl(C₁-C₄ alkyl)-, aryl, and aryl(C₁-C₁₀ alkyl)-; R²¹ and R²² areeach independently H, methyl, ethyl, propyl, or butyl; R²³ is selectedfrom: H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, hydroxy, C₁-C₆ alkoxy, benzyloxy, aryl, aryl(C₁-C₄alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl)-, adamantylmethyl, andC₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R²⁴ is selected from: C₁-C₈alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R²⁵ andR²⁶ are, independently, selected from: H, C₁-C₁₀ alkyl, C₁-C₁₀alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkylsulfonyl, aryl,aryl(C₁-C₄ alkyl)-, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, aryl(C₁-C₁₀ alkyl)sulfonyl, aryl(C₂-C₁₀alkenyl)sulfonyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₃-C₁₀ cycloalkoxycarbonyl, C₇-Cl,bicycloalkoxycarbonyl, heteroaryl, heteroarylcarbonyl,heteroarylsulfonyl, and heteroaryl(C₁-C₄ alkyl)carbonyl, wherein saidaryl groups are optionally substituted with 1-3 substituents selectedfrom the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andNO₂; R²⁷ is selected from H, methyl, ethyl, propyl, butyl, benzyl,phenethyl, cyclopropyl, and cyclopropylmethyl; R²⁸ and R²⁹ areindependently selected from: H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl), aryl(C₀-C₄ alkyl), and heteroaryl(C₀-C₄ alkyl),wherein said aryl or heteroaryl groups are substituted with 0-2substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, F,Cl, Br, CF₃, and NO₂; n is 0, 1, or 2; q is 1, 2, 3, or 4; r is 0, 1, or2; and s is 1, 2, 3, or
 4. 2. A compound of Formula (Ib):

or a pharmaceutically acceptable salt form thereof wherein: b is asingle or double bond; R¹ is selected from R^(2a)(R³)N—V—,R^(2a)(R³)N(CH₂)_(q)—, R²(R^(2b))N(R³N═)C—V—,R²(R^(2b))N(R³N═)C(CH₂)_(q)—, R²(R^(2b))N(R³N═)CNH—V—,R²(R¹¹O)N(R³N═)C—V—, R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from: -(C₁-C₄ alkyl)-, -(C₂-C₄ alkenyl)-, -(C₂-C₄alkynyl)-, -(phenyl)-, said phenyl substituted with 0-2 groupsindependently selected from R⁹, -(pyridyl)-, said pyridyl substitutedwith 0-2 groups independently selected from R⁹, or -(pyridazinyl)-, saidpyridazinyl substituted with 0-2 groups independently selected from R⁹;Z is selected from: a bond, O, S, S(═O), and S(═O)₂; R^(2a) is R² orR²(R^(2b))N(R³N═)C—; R², R^(2b), and R³ are independently selected from:H, C₁-C₁₀ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄ haloalkyl, aryl,arylcarbonyl, aryl(C₁-C₄ alkyl)-, diarylmethyl, 2,2-diarylethyl,benzhydryl(C₁-C₄ alkyl)-, heteroaryl, heteroaryl(C₁-C₅ alkyl)-, and acleavable protecting group selected from: C₁-C₆ alkoxycarbonyl, C₃-C₁₁cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryloxycarbonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, (C₁-C₆ alkyl)carbonyloxy(C₁-C₄alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and (C₃-C₁₁cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl, wherein at least one ofR^(2b), R^(2b), and R³ is H or a cleavable protecting group; whereinsaid aryl groups of R², R^(2b), and R³ may be substituted with 0-3groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃,—CN, —SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl), —SO₂NH₂, —NR²¹R²², C₁-C₄haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl; and  saidheteroaryl groups of R², R^(2b), and R³ may be substituted with 0-2groups selected from hydroxy, halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃,SO₂CH₃, and —NR²¹R²²; alternatively, R² and R^(2b) can be taken togetherwith the nitrogen atom to which they are attached to form a 5-14membered heterocyclic ring optionally containing one additionalheteroatom selected from: N, O, or S; said heterocyclic ring beingmonocyclic, bicyclic, or tricyclic; said heterocyclic ring beingsubstituted with 0-3 R⁴; R⁴, when a substituent on carbon, isindependently selected from H, C₁-C₄ alkyl, aryl, aryl(C₁-C₆ alkyl)-,C₁-C₄ alkoxy, halogen, methylenedioxydiyl, (C₁-C₆ alkyl)SO₂NH—, (C₆-C₁₁aryl)SO₂NH—, (C₁-C₆ alkyl)CONH—, (C₆-Cl, aryl)CONH—, (C₁-C₆ alkyl)NHCO—,(C₆-Cl, aryl)NHCO—, (C₁-C₆ alkyl)NHSO₂—, (C₆-Cil aryl)NHSO₂—, (C₁-C₆alkyl)SO₂—, (C₆-C₁₁ aryl)SO₂—, wherein said aryl groups may beoptionally substituted with 0-3 groups selected from hydroxy, halogen,C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, OCF₃, SCH₃, S(O)CH₃, SO₂CH₃, —NR²¹R²²,C₁-C₄ haloalkyl, methylenedioxydiyl, and ethylenedioxydiyl;alternatively, when two R⁴ groups are attached to adjacent carbon atoms,they may be taken together with the atoms to which they are attached toform a fused 5-7 membered saturated, unsaturated or aromatic carbocyclicring; alternatively, when R⁴ is attached to a saturated carbon atom, itmay also be ═O or ═S; R⁴, when a substituent on nitrogen, isindependently selected from H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₁-C₁₀alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkylsulfonyl, C₃-C₁₀cycloalkyl, C₃-C₁₀ cycloalkyl(C₁-C₄ alkyl)-, C₃-C₁₁ cycloalkoxycarbonyl,C₇-C₁₁ bicycloalkoxycarbonyl, aryl, aryl(C₁-C₁₀ alkyl)-, diarylmethyl,2,2-diarylethyl, benzhydryl(C₁-C₄ alkyl)-, arylcarbonyl,aryloxycarbonyl, arylsulfonyl, aryl(C₁-C₁₀ alkyl)sulfonyl, aryl(C₂-C₁₀alkenyl)sulfonyl, aryl(C₁-C₁₀ alkoxy)carbonyl, heteroaryl,heteroarylsulfonyl, heteroarylcarbonyl, heteroaryl(C₁-C₁₀ alkyl)-, andheteroaryl(C₁-C₁₀ alkyl)carbonyl, wherein said aryl or heteroaryl groupsmay be additionally substitututed with 0-2 groups selected from hydroxy,halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, SCH₃, SOCH₃, SO₂CH₃, or—NR²¹R²²; R⁴, when a substituent on sulfur, may be ═O; X is—CH₂—CH(W^(a))—, —CH(W^(b))—CH₂— or —CH(W^(b))—; Y is selected fromhydroxy, C₁-C₁₀ alkyloxy, C₃-C₁₁ cycloalkyloxy, C₆-C₁₀ aryloxy, C₇-C₁₁arylalkyloxy, C₂-C₁₀ alkylcarbonyloxyalkyloxy, C₂-C₁₀alkoxycarbonyloxyalkyloxy, C₂-C₁₀ alkoxycarbonylalkyloxy, C₄-C₁₀cycloalkylcarbonyloxyalkyloxy, C₄-C₁₀ cycloalkoxycarbonyloxyalkyloxy,C₄-C₁₀ cycloalkoxycarbonylalkyloxy, C₇-C₁₁ aryloxycarbonylalkyloxy,C₇-C₁₂ aryloxycarbonyloxyalkyloxy, C₇-C₁₂ arylcarbonyloxyalkyloxy,C₄-C₁₀ alkoxyalkylcarbonyloxyalkyloxy, (5-(C₁-C₄alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R²⁸)(R²⁹)N-(C₁-C₁₀ alkoxy)-; W^(a) is selected from: H, hydroxy, —NR¹⁶R²⁰,—NR²⁵R²⁶, C₁-C₁₀ alkoxy, C₁-C₁₀ alkyl substituted with 0-3 R⁸, and arylsubstituted with 0-3 R⁸; W^(b) is selected from: H, CH₂OH, CH₂OR¹²,CH₂CO₂R¹², CH₂C(═O)NHR¹⁸, CH₂NR¹⁶R²⁰, CH₂NR²⁵R²⁶, C₃-C₆ alkenyl, C₃-C₁₀cycloalkyl, C₄-C₁₁ cycloalkylmethyl, pyridyl; and C₁-C₈ alkylsubstituted with 0-2 R⁸; aryl substituted with 0-3 R⁸; and aryl(C₁-C₆alkyl), said aryl substituted with 0-3 R⁸; R⁵ is selected from: H, C₃-C₆alkenyl, C₄-Cli cycloalkylmethyl, aryl(C₁-C₆ alkyl)-, and C₁-C₈ alkylsubstituted with 0-2 R⁸, R⁶ is H or methyl; alternatively, R⁵ and R⁶ canbe taken together to be ═O; R^(7a) and R^(7b) are independently selectedfrom H, methyl, ethyl, and ═O; alternatively, when R^(7a) and R^(7b)occur on adjacent carbons R⁷a and R^(7b) may be taken together to form asix carbon aromatic ring; R⁸ is selected from: H, hydroxy, cyano,—CO₂R¹², —C(═O)R¹³, —OC(═O)R¹³, —OC(═O)OR¹⁴, —OR¹², —OCH₂CO₂R¹²,—CO₂CH₂CO₂R¹², —OC(═O)NR²³R²⁴, —C(═O)NR²³R²⁴, —NR²⁵R²⁶, —NR²⁷C(═O)R¹³,—NR²⁷C(═O)OR¹⁴, —NR²⁷SO₂R¹⁴, —SR¹⁴, —SOR¹⁴, —SO₂R¹⁴, —SO₂NR²³R²⁴, C₁-C₁₀alkoxy, C₁-C₁₀ alkylcarbonyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe and —NMe₂, aryl(C₁-C₄ alkyl)-, wherein said aryl issubstituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, CO₂R¹², SO₂Me, SOMe, SMe, and —NMe₂, and a 5-10 memberedheterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein saidheterocyclic ring may be saturated, partially saturated, or fullyunsaturated, said heterocyclic ring being substituted with 0-2 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe and —NMe₂; R^(8a) is selected from: H, cyano, —CO₂R¹²,—C(═O)R¹³, —C(═O)NR²³R²⁴, C₁-C₁₀ alkylcarbonyl, C₂-C₆ alkenyl, C₃-C₁₀cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl, wherein said aryl issubstituted with 0-3 groups selected from halogen, C₁-C₆ alkoxy, C₁-C₆alkyl, CF₃, CO₂R¹², SO₂Me, SOMe, SMe and —NMe₂, and aryl(C₁-C₄ alkyl)-,wherein said aryl is substituted with 0-3 groups selected from halogen,C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me, SOMe, SMe, and —NMe₂; R⁹is selected from H, halogen, CF₃, CN, C₁-C₄ alkyl, and C₁-C₄ alkoxy; R¹⁰is selected from: H, hydroxy, CN, carboxy, —NR²⁵R²⁶; C₁-C₆ alkyl, C₂-C₆alkenyl, C₂-C₆ alkynyl, C₃-C₇ cycloalkyl, C₇-C₁₄ bicycloalkyl, C₁-C₆alkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulfinyl, C₁-C₆ alkylsulfonyl, C₁-C₆alkylcarbonyl, C₁-C₆ alkoxycarbonyl, aryl, piperidinyl, morpholinyl, andpyridinyl; R¹¹ is selected from: H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, andC₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R¹² is selected from: H, C₁-C₈alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R¹³ isselected from: hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl,C₄-C₁₁ cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, heteroaryl,heteroaryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R¹⁴is selected from: C₁-C₈ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, aryl, aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substitutedwith 1-2 R¹⁰; R¹⁵ is selected from: H, OH, —OR¹², —CO₂R¹²,—C(═O)NR²³R²⁴, —OC(═O)NR²³R²⁴, C₁-C₁₀ alkoxycarbonyl substituted with0-2 R⁸; C₁-C₁₀ alkyl substituted with 0-3 R⁸; C₂-C₁₀ alkenyl substitutedwith 0-3 R⁸; and C₁-C₁₀ alkoxy substituted with 0-3 R⁸; R¹⁶ is selectedfrom: —C(═O)OR¹⁷, —C(═O)R¹⁸, —C(═O)NR¹⁷R¹⁸, —C(═O)NHSO₂R¹⁷,—C(═O)NHC(═O)R¹⁷, —C(═O)NHC(═O)OR¹⁷, —C(═O)NHSO₂NHR¹⁷, —SO₂R¹⁷,—SO₂NR¹⁷R¹⁸, and —SO₂NHC(═O)OR¹⁷; R¹⁷ is selected from: C₁-C₈ alkylsubstituted with 0-2 R¹⁹, C₃-C₈ alkenyl substituted with 0-2 R¹⁹, C₃-C₈alkynyl substituted with 0-2 R¹⁹, C₃-C₈ cycloalkyl substituted with 0-2R¹⁹, aryl substituted with 0-4 R¹⁹, aryl(C₁-C₆ alkyl)- substituted with0-4 R¹⁹, a 5-10 membered heterocyclic ring system having 1-3 heteroatomsselected independently from 0, S, and N, said heterocyclic ring beingsubstituted with 0-4 R¹⁹, and C₁-C₆ alkyl substituted with a 5-10membered heterocyclic ring system having 1-3 heteroatoms selectedindependently from 0, S, and N, said heterocyclic ring being substitutedwith 0-4 R¹⁹; R¹⁸ is selected from H and R¹⁷; R¹⁹ is selected from: H,halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₆ alkyl)-, C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl; R²⁰ isselected from: H, C₁-C₁₀ alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₃-C₁₁cycloalkyl(C₁-C₄ alkyl)-, aryl, and aryl(C₁-C₁₀ alkyl)-; R²¹ and R²² areeach independently H, methyl, ethyl, propyl, or butyl; R²³ is selectedfrom: hydrogen, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁cycloalkylmethyl, hydroxy, C₁-C₆ alkoxy, benzyloxy, aryl, aryl(C₁-C₄alkyl)-, heteroaryl, heteroaryl(C₁-C₄ alkyl)-, adamantylmethyl, andC₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R²⁴ is selected from: C₁-C₈alkyl, C₂-C₆ alkenyl, C₃-C₁₁ cycloalkyl, C₄-C₁₁ cycloalkylmethyl, aryl,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R²⁵ andR²⁶ are, independently, selected from: H, C₁-C₁₀ alkyl, C₁-C₁₀alkoxycarbonyl, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkylsulfonyl, aryl,aryl(C₁-C₄ alkyl)-, arylcarbonyl, aryloxycarbonyl, arylsulfonyl,aryl(C₁-C₁₀ alkoxy)carbonyl, aryl(C₁-C₁₀ alkyl)sulfonyl, aryl(C₂-C₁₀alkenyl)sulfonyl, C₂-C₆ alkenyl, C₃-C₁₀ cycloalkyl, C₃-C₁₀cycloalkyl(C₁-C₄ alkyl)-, C₃-C₁₀ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl, heteroaryl, heteroarylcarbonyl,heteroarylsulfonyl, and heteroaryl(C₁-C₄ alkyl)carbonyl, wherein saidaryl groups are optionally substituted with 1-3 substituents selectedfrom the group consisting of: C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, CF₃, andNO₂; R²⁷ is selected from H, methyl, ethyl, propyl, butyl, benzyl,phenethyl, cyclopropyl, and cyclopropylmethyl; R²⁸ and R²⁹ areindependently selected from: H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₁₀cycloalkyl(C₀-C₄ alkyl), aryl(C₀-C₄ alkyl), and heteroaryl(C₀-C₄ alkyl),wherein said aryl or heteroaryl groups are substituted with 0-2substituents independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy, F,Cl, Br, CF₃, and NO₂; n is 0, 1, or 2; q is 1, 2, 3, or 4; r is 0, 1, or2; and s is 1, 2, 3, or
 4. 3. A compound according to claim 2 wherein: bis a single or double bond; R¹ is selected from R^(2a)(R³)N—V—,R²(R^(2b))N(R³N═)C—V—, R²(R^(2b))N(R³N═)CNH—V—, R²(R¹¹O)N(R³N═)C—V—,R²(R^(2b))N(R¹¹ON═)C—V—,

V is selected from: -(C₁-C₄ alkyl)-, -(phenyl)-, said phenyl substitutedwith 0-2 groups independently selected from R⁹, -(pyridyl)-, saidpyridyl substituted with 0-2 groups independently selected from R⁹, or-(pyridazinyl)-, said pyridazinyl substituted with 0 -2 groupsindependently selected from R⁹; Z is selected from: a bond, 0, andS(═O)₂; W^(a) is selected from: H, hydroxy, —NHR¹⁶, —NR²⁵R²⁶, C₁-C₁₀alkoxy, C₁-C₁₀ alkyl substituted with 0-3 R⁸, and aryl substituted with0-3 R⁸, R⁶ is H; alternatively, R⁵ and R⁶ can be taken together to be═O; R^(7a) and R^(7b) are independently H or ═O; R¹² is selected from H,aryl(C₁-C₄ alkyl)-, and C₁-C₁₀ alkyl substituted with 1-2 R¹⁰; R¹⁵ isselected from: H, OH, —OR¹², —CO₂R¹², —C(═O)NR²³R²⁴, and —OC(═O)NR²³R²⁴;R¹⁶ is selected from —C(═O)OR¹⁷, —C(═O)R¹⁸, —SO₂R¹⁷, and —SO₂NR¹⁷R¹⁸;R¹⁷ is selected from: C₁-C₈ alkyl substituted with 0-2 R¹⁹, C₃-C₈alkenyl substituted with 0-2 R¹⁹, C₃-C₈ alkynyl substituted with 0-2R¹⁹, C₃-C₈ cycloalkyl substituted with 0-2 R¹⁹, aryl substituted with0-4 R¹⁹, aryl(C₁-C₆ alkyl)- substituted with 0-4 R¹⁹, a 5-10 memberedheterocyclic ring system selected from pyridinyl, furanyl, thiazolyl,thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl,indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl,benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl,3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, saidheterocyclic ring being substituted with 0-4 R¹⁹, said heterocyclic ringbeing substituted with 0-4 R¹⁹, and C₁-C₆ alkyl substituted with a 5-10membered heterocyclic ring system selected from pyridinyl, furanyl,thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, or piperazinyl, saidheterocyclic ring being substituted with 0-4 R¹⁹; R¹⁸ is selected from Hand C₁-C₅ alkyl; n is 0, 1 or 2; q is 1, 2, 3, or 4; r is 0, 1, or 2;and s is 1, 2, 3, or
 4. 4. A compound according to claim 3 wherein: b isa single or double bond; R¹ is selected from R²(R²b)N(R³N═)C—V—,R²(R^(2b))N(R³N═)CNH—V—,

V is selected from: -(C₁-C₄ alkyl)-, -(pyridyl)-, and -(phenyl)-, saidphenyl substituted with 0-2 groups independently selected from F. Br,methyl, and methoxy; Z is a bond or O; R², R^(2b), and R³ areindependently selected from: H, C₁-C₈ alkyl, C₃-C₆ alkenyl, C₃-C₆alkynyl, C₃-C₈ cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇alkylcarbonyl, C₁-C₄ haloalkyl, aryl, arylcarbonyl, 2C) aryl(C₁-C₄alkyl)-, diarylmethyl, 2,2-diarylethyl, benzhydryl(C₁-C₄ alkyl)-,heteroaryl, heteroaryl(C₁-C₄ alkyl)-, and a cleavable protecting groupselected from: C₁-C₆ alkoxycarbonyl, C₃-C₈ cycloalkoxycarbonyl, C₇-C₁₁bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C₁-C₈ alkoxy)carbonyl,(C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl, arylcarbonyloxy(C₁-C₄alkoxy)carbonyl, and (C₃-C₈ cycloalkyl)carbonyloxy(C₁-C₄alkoxy)carbonyl, wherein at least one of R², R^(2b), and R³ is H or acleavable protecting group; wherein said aryl groups of R², R^(2b), andR³ may be substituted with 0-3 groups selected from hydroxy, halogen,C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, —CN, —SO₂(C₁-C₄ alkyl), —S(C₁-C₄ alkyl),—SO₂NH₂, —NR²¹R²², C₁-C₄ haloalkyl, methylenedioxydiyl, andethylenedioxydiyl; and  said heteroaryl groups of R², R^(2b), and R³ maybe substituted with 0-2 groups selected from hydroxy, halogen, C₁-C₆alkoxy, C₁-C₆ alkyl, CF3, SO₂CH₃, and —NR²¹R²²; alternatively, R² andR^(2b) can be taken together with the nitrogen atom to which they areattached to form a 5-14 membered heterocyclic ring system selected frommorpholine, piperidine, piperazine, pyrrolidine, tetrahydroisoquinoline,thiazolidine, thiomorpholine, 1,4-benzoxazine,8-oxo-3-aza-bicyclo[3.2.1]octane, 2,6-dimethylmorpholine,2,6-dimethylpiperazine, 1,2,3,4-tetrahydro-2,7—Naphthyridine,1,4-dioxa-8-azaspiro[4.5]decane, azepine, or2,3-dihydro-1H-benzo[de]isoquinoline, said heterocyclic ring beingsubstituted with 0-3 R⁴; X is —CH₂—CH(W^(a))— or —CH(W^(b))—; Y isselected from hydroxy, hydroxy; C₁-C₆ alkoxy; methylcarbonyloxymethoxy-;ethylcarbonyloxymethoxy-; t-butylcarbonyloxymethoxy-;cyclohexylcarbonyloxymethoxy-; 1-(methylcarbonyloxy)ethoxy-;1-(ethylcarbonyloxy)ethoxy-; 1-(t-butylcarbonyloxy)ethoxy-;1-(cyclohexylcarbonyloxy)ethoxy-; i-propyloxycarbonyloxymethoxy-;t-butyloxycarbonyloxymethoxy-; 1-(i-propyloxycarbonyloxy)ethoxy-;1-(cyclohexyloxycarbonyloxy)ethoxy-; 1-(t-butyloxycarbonyloxy)ethoxy-;dimethylaminoethoxy-; diethylaminoethoxy-;(5-methyl-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;(5-(t-butyl)-1,3-dioxacyclopenten-2-on-4-yl)methoxy-;(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; W^(a) is H or —NHR¹⁶; R⁶ isH; alternatively, R⁵ and R⁶ can be taken together to be ═O; R^(7a) andR^(7b) are independently H or ═O; W^(b) is selected from: H, methyl,ethyl, benzyl, phenethyl, pyridyl, pyridylmethyl, CH₂C(═O)NHR¹⁸, andCH₂NHR¹⁶; R⁸ is selected from: H, hydroxy, cyano, —CO₂R¹², —C(═O)R ³,—C(═O)NR²³R²⁴, —NR²⁵R²⁶, —SR¹⁴, —SOR¹⁴, —SO₂R¹⁴, C₁-C₁₀ alkoxy, C₁-C₁₀alkylcarbonyl, aryl, wherein said aryl is substituted with 0-3 groupsselected from halogen, C₁-C₆ alkoxy, C₁-C₆ alkyl, CF₃, CO₂R¹², SO₂Me,SOMe, SMe and —NMe₂, a 5-10 membered heterocyclic ring system selectedfrom pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl,triazolyl, imidazolyl, benzofuranyl, indolyl, inolinyl, quinolinyl,isoquinolinyl, benzimidazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,3H-indolyl, pyrrolidinyl, piperidinyl, isoxazolinyl, isoxazolyl andmorpholinyl; R¹⁵ is selected from H, OH, —OR¹², and —OC(═O)NR²³R²⁴; R¹⁶is —C(═O)OR¹⁷ or —SO₂R¹⁷; R¹⁷ is selected from: C₁-C₈ alkyl, C₂-C₈alkenyl, aryl substituted with 0-4 R¹⁹, aryl(C₁-C₆ alkyl)- substitutedwith 0-4 R¹⁹, a 5-10 membered heterocyclic ring system selected frompyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl, pyrazolyl, triazolyl,imidazolyl, benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl,isoxazolyl, isoxazolinyl, benzyimdazolyl, piperidinyl,tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl, pyrrolidinyl,morpholinyl, and piperazinyl, said heterocyclic ring being substitutedwith 0-4 R¹⁹, said heterocyclic ring being substituted with 0-4 R¹⁹, andC₁-C₆ alkyl substituted with a 5-10 membered heterocyclic ring systemselected from pyridinyl, furanyl, thiazolyl, thienyl, pyrrolyl,pyrazolyl, triazolyl, imidazolyl, benzofuranyl, indolyl, indolinyl,quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl, benzyimdazolyl,piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl, 3H-indolyl,pyrrolidinyl, morpholinyl, and piperazinyl, said heterocyclic ring beingsubstituted with 0-4 R¹⁹; R¹⁹ is selected from: H, halogen, CF₃, CN,NO₂, NR²⁵R²⁶, C₁-C₈ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, C₃-C₁₁cycloalkyl, C₃-C₁₁ cycloalkyl(C₁-C₄ alkyl)-, aryl, aryl(C₁-C₆ alkyl)-,C₁-C₆ alkoxy, and C₁-C₄ alkoxycarbonyl; n is 1 or 2; q is 1, 2, 3, or 4;r is 0, 1, or 2; and s is 1, 2, 3, or
 4. 5. A compound according toclaim 4 wherein: b is a single bond; R¹ is R²(R^(2b))N(R³N=)C—V— orR²(R²b)N(R³N═)CNH—V—; V is -(pyridyl)- or -(phenyl)-, said phenylsubstituted with 0-2 groups independently selected from F, Br, methyl,and methoxy; Z is a bond or O; R², R^(2b), and R³ are independentlyselected from: H, C₁-C₆ alkyl, C₃-C₆ alkenyl, C₃-C₆ alkynyl, C₃-C₈cycloalkyl, C₃-C₈ cycloalkyl(C₁-C₄ alkyl)-, C₂-C₇ alkylcarbonyl, C₁-C₄haloalkyl, arylcarbonyl, aryl(C₁-C₄ alkyl)-, diarylmethyl,2,2-diarylethyl, heteroaryl, heteroaryl(C₁-C₄ alkyl)-, and a cleavableprotecting group selected from: C₁-C₄ alkoxycarbonyl, C₃-C₆cycloalkoxycarbonyl, C₇-C₁₁ bicycloalkoxycarbonyl, aryl(C₁-C₈alkoxy)carbonyl, (C₁-C₆ alkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl,arylcarbonyloxy(C₁-C₄ alkoxy)carbonyl, and (C₃-C₈cycloalkyl)carbonyloxy(C₁-C₄ alkoxy)carbonyl, wherein at least one ofR², R^(2b), and R³ is H or a cleavable protecting group; wherein saidaryl groups of R², R^(2b), and R³ may be substituted with 0-3 groupsselected from hydroxy, halogen, methoxy, ethoxy, propoxy, butoxy,methyl, ethyl, propyl, butyl, CF₃, —CN, —SO₂(CH₃), —SO₂(C₂H₅),SO₂(C₃H₇), —SO₂(C₄H₉), —SO₂NH₂, —NR²¹R²², C₁-C₄ haloalkyl,methylenedioxydiyl, and ethylenedioxydiyl; and  said heteroaryl groupsof R², R^(2b), and R³ may be substituted with 0-2 groups selected fromhydroxy, halogen, methoxy, ethoxy, propoxy, butoxy, methyl, ethyl,propyl, butyl, CF₃, SO₂CH₃, and —NR²¹R²²; alternatively, R² and R^(2b)can be taken together with the nitrogen atom to which they are attachedto form a 5-14 membered heterocyclic ring system selected frommorpholine, piperidine, piperazine, pyrrolidine, tetrahydroisoquinoline,thiazolidine, thiomorpholine, 1,4-benzoxazine,8-oxo-3-aza-bicyclo[3.2.1]octane, 2,6-dimethylmorpholine,2,6-dimethylpiperazine, 1,2,3,4-tetrahydro-2,7—Naphthyridine,1,4-dioxa-8-azaspiro[4.5]decane, azepine, or2,3-dihydro-1H-benzo[de]isoquinoline, said heterocyclic ring beingsubstituted with 0-2 R⁴; R⁴, when a substituent on carbon, isindependently selected from H, F, Cl, methyl, ethyl, propyl, butyl,methoxy, ethoxy, methylenedioxydiyl, —NH₂, —NHSO₂CH₃, —NHSO₂C₂H₅,—NHSO₂C₃H₇, —NHSO₂(phenyl), —NHC(═O)CH₃, —NHC(═O)C₂H₅, and phenyl;wherein said phenyl groups may be optionally substituted with 0-3 groupsselected from hydroxy, halogen, methoxy, methyl, ethyl, CF₃, SCH₃, —NH₂,—NH(CH₃), —N(CH₃)2, methylenedioxydiyl, and ethylenedioxydiyl;alternatively, when two R⁴ groups are attached to adjacent carbon atoms,they may be taken together with the atoms to which they are attached toform a fused 5-7 membered saturated, unsaturated or aromatic carbocyclicring; alternatively, when R⁴ is attached to a saturated carbon atom, itmay also be ═O or ═S; R⁴, when a substituent on nitrogen, isindependently selected from: H, methyl, ethyl, propyl, butyl,cyclopropyl, cyclopropylmethyl, phenyl, phenylmethyl, phenylethyl,pyridyl, pyridylmethyl, wherein said phenyl or pyridyl groups may beadditionally subsetitututed with 0-2 groups selected from hydroxy,halogen, methoxy, methyl, ethyl, CF₃, SCH₃, —NH₂, —NH(CH₃), and—N(CH₃)₂; R⁴, when a substituent on sulfur, may be ═O; X is—CH₂—CH(W^(a))— or —CH(W^(b))—; Y is selected from hydroxy; methoxy;ethoxy; isopropoxy; n-butyloxy; isobutyloxy; t-butoxy; benzyloxy;methylcarbonyloxymethoxy-; ethylcarbonyloxymethoxy-;t-butylcarbonyloxymethoxy-; cyclohexylcarbonyloxymethoxy-;1-(methylcarbonyloxy)ethoxy-; 1-(ethylcarbonyloxy)ethoxy-;1-(t-butylcarbonyloxy)ethoxy-; 1-(cyclohexylcarbonyloxy)ethoxy-;i-propyloxycarbonyloxymethoxy-; t-butyloxycarbonyloxymethoxy-;1-(i-propyloxycarbonyloxy)ethoxy-; 1-(cyclohexyloxycarbonyloxy)ethoxy-;1-(t-butyloxycarbonyloxy)ethoxy-; dimethylaminoethoxy-;diethylaminoethoxy-; (5-methyl-1,3-dicoxacyclopenten-2-on-4-yl)methoxy-;(5-(t-butyl)-1,3—dioxacyclopenten-2-on-4-yl)methoxy-;(1,3-dioxa-5-phenyl-cyclopenten-2-on-4-yl)methoxy-;1-(2-(2-methoxypropyl)carbonyloxy)ethoxy-; W^(a) is H or —NHR¹⁶; R⁶ isH; alternatively, R⁵ and R⁶ can be taken together to be ═O; R^(7a) andR^(7b) are independently H or ═O; W^(b) is H, methyl, ethyl, benzyl,phenethyl, pyridyl, pyridylmethyl, CH₂C(═O)NHR¹⁸, and CH₂NHR¹⁶; R⁸ isselected from: H, hydroxy, cyano, —CO₂R¹², —C(═O)R¹³, —C(═O)NR²³R²⁴,—NR²⁵R²⁶, —SR¹⁴, —SOR¹⁴, —SO₂R¹⁴, C₁-C₄ alkoxy, C₁-C₄ alkylcarbonyl,aryl, wherein said aryl is substituted with 0-3 groups selected fromhalogen, methoxy, ethoxy, propoxy, butoxy, methy-L, ethyl, propyl,butyl, CF₃, CO₂R¹², SO₂Me, SOMe, SMe and —NMe₂, a 5-10 memberedheterocyclic ring system selected from pyridinyl, fu:ranyl, thiazolyl,thienyl, pyrrolyl, pyrazolyl, tr:iazolyl, imidazolyl, benzofuranyl,indolyl, inolinyl, quinolinyl, isoquinolinyl, benzimidazoly1,piperidinyl, tetrahydrofuranyl, pyranyl, 3H-i:ndolyl, pyrrolidinyl,piperidinyl, isoxazolinyl, isoxazolyl and morpholinyl; R¹⁵ is H; R¹⁶ is—SO₂R¹⁷, —C(═O)OCH₂CH₂CH₂CH₃, —C(═O)OCH₂CH(CH₃)₂ or —C(═O)OCH₂(C₆H₅);R¹⁷ is selected from: C₁-C₈ alkyl, aryl substituted with 0-2 R¹⁹,aryl(C₁-C₆ alkyl)- substituted with 0-2 R¹⁹, a 5-10 memberedheterocyclic ring system selected from pyridinyl, furanyl, thiazolyl,thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl, benzofuranyl,indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl, isoxazolinyl,benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl, pyrimidinyl,3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl, saidheterocyclic ring being substituted with 0-2 R¹⁹, said heterocyclic ringbeing substituted with 0-2 R¹⁹, and C₁-C₆ alkyl substituted with a 5-10membered heterocyclic ring system selected from pyridinyl, furanyl,thiazol-yl, thienyl, pyrrolyl, pyrazolyl, triazolyl, imidazolyl,benzofuranyl, indolyl, indolinyl, quinolinyl, isoquinolinyl, isoxazolyl,isoxazolinyl, benzyimdazolyl, piperidinyl, tetrahydrofuranyl, pyranyl,pyrimidinyl, 3H-indolyl, pyrrolidinyl, morpholinyl, and piperazinyl,said heterocyclic ring being substituted with 0-2 R¹⁹; R¹⁹ is selectedfrom: H, halogen, CF₃, CN, NO₂, NR²⁵R²⁶, C₁-C₄ alkyl, C₂-C₄ alkenyl,C₂-C₄ alkynyl, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyl(C₁-C₄ alkyl)-, aryl,aryl(C₁-C₄ alkyl)-, C₁-C₄ alkoxy, and C₁-C₄ alkoxycarbonyl; n is 1; ands is 1 or
 2. 6. A compound of claim 2 selected from the group:2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(n-butylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(phenylmethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(n-propylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(ethylamino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(piper.dino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(thiazolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2,6-d:imethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylimethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(4-methylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmnethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(4-phenylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmnethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(pyrrolidino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolir.-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydro-2,7—Naphthyridino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,4-dioxa-8-azaspiro[4.5]decyl)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2,6-dimethylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(4-(2-fluorophenyl)piperazino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(4-(2-methylphenyl)piperazino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(thiomorpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[2-(2-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(4-propylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmrethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(4-benzylpiperazino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-(aminoim-inomethyl)phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(morphophino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2,6-diinethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-2-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylme~thyl]-3-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-3-oxo-piperazin-1-yl]aceticacid,2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazol-5-ylmetliyl]piperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazol-5-ylmethyl]piperazin-1-yl]aceticacid,2-[4-[3-[4-(aminoircinomethyl)phenyl]isoxazolin-5-ylmethyl]-[1,4]d~iazepan-1-yl]aceticacid,2-[4-[3-[4-[(morphcolino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-[1,4]d.iazepan-1-yl]aceticacid,2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-[1,4]diazepan-1-yl]aceticacid,2-[4-[3-[4-(aminoiminomethyl)phenyl]isoxazolin-5-ylmethyl]-2,6-dimiethylpiperazin-1-yl]aceticacid,2-[4-[3-[4-[(morpholino)iminomethyl]phenyl]isoxazolin-5-ylmethyl]-2,6-dirnethylpiperazin-1-yl]aceticacid,2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,2-[4-[3-[4-[(2-phenylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylm(ethyl]-2,6-dimethylpiperazin-1-yl]aceticacid,2-[4-[3-(1-aminoiminomethylpiperidin-4-yl)-isoxazolin-5-ylmethyl]-pipera:zin-1-yl]-aceticacid,2-[4-[3-[4-[(N-methyl-N-phenethylamino)iminomethyl]-phenyl]-isoxazol~in-5-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-(4-benzylarninoiminomethylphenyl)-isoxazolin-5-ylmethyl]-piperazin-l-yl]-aceticacid,2-[4-[3-[4-(2,2-diphenylethylamino)iminomethylphenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-[2-(3-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-(3-pyridylmethylamino)iminomethylphenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-[2-(4-chlorophenylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-[2-(imidazol-4-ylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-[2-(4-aminosulfonylphenylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-C₁-yl]-aceticacid,2-[4-[3-[4-[2-(4-fluorophenylethylamino)iminomethyl]-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-[2-(4-methoxyphenylethylamino)iminomethyl]-phenyl]-isoxazolhn-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-(2-indanoiminomethyl)-phenyl]-isoxazolin-5-ylmethyl]-piperazin-1-yl]-aceticacid,2-[4-[3-[4-[(4-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(3,4-methylenedioxy-1,2,3,4-tetrahydroisoquiriolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4—piperazin-1-yl]aceticacid,2-[4-[3-[4-[(6,7-dimethoxy-1,2,3,4-tetrahydroisoquiriolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(6-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(8-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(7-chloro-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(5-methoxy-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(6,7-methylenedioxy-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4—piperazin-1-yl]aceticacid,2-[4-[3-[4-[(7-fluoro-1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(7-methylsulfonylamino-1,2,3,4-tetrahydroisoquiriolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4—piperazin-1-yl]aceticacid,2-[4-[3-[4-[(5-methylsulfonylamino-1,2,3,4-tetrahydroisoquiriolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4—piperazin-1-yl]aceticacid,2-[4-[3-[4-[(7-phenylsulfonylamino-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4—piperazin-1-yl]aceticacid,2-[4-[3-[4-[(5-acetylamino-1,2,3,4-tetrahydroisoquinolino)-iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4—piperazin-1-yl]aceticacid,2-[4-[3-[4-[(1,2,3,4-tetrahydroisoquinolino)iminomethyl]-phenyl]isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid,2-[4-[3-[4-[(2,6-dimethylmorpholino)iminomethyl]phenyl]-isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]acetic acid, and2-[4-[3-[4-[2-(4-pyridylethylamino)iminomethyl]phenyl]-isoxazolin-5(R)-ylmethyl]-4-piperazin-1-yl]aceticacid.
 7. A compound according to claim 6 wherein the stereochemistry ofthe isoxazolin-5-ylmethyl moiety is isoxazolin-5(S)-ylmethyl.
 8. Acompound according to claim 6 wherein the stereochemistry of theisoxazolin-5-ylmethyl moiety is isoxazolin-5(R)-ylmethyl.
 9. Apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a therapeutically effective amount of a compound of claim 1or a pharmaceutically acceptable salt form thereof.
 10. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 2 or apharmaceutically acceptable salt form thereof.
 11. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 3 or apharmaceutically acceptable salt form thereof.
 12. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 4 or apharmaceutically acceptable salt form thereof.
 13. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 5 or apharmaceutically acceptable salt form thereof.
 14. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 6 or apharmaceutically acceptable salt form thereof.
 15. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 7 or apharmaceutically acceptable salt form thereof.
 16. A pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atherapeutically effective amount of a compound of claim 8 or apharmaceutically acceptable salt form thereof.
 17. A method ofinhibiting the aggregation of blood platelets which comprisesadministering to a host in need of such inhibition a therapeuticallyeffective amount of a compound of claim
 1. 18. A method of inhibitingthe aggregation of blood platelets which comprises administering to ahost in need of such inhibition a therapeutically effective amount of acompound of claim
 2. 19. A method of inhibiting the aggregation of bloodplatelets which comprises administering to a host in need of suchinhibition a therapeutically effective amount of a compound of claim 3.20. A method of inhibiting the aggregation of blood platelets whichcomprises administering to a host in need of such inhibition atherapeutically effective amount of a compound of claim
 4. 21. A methodof inhibiting the aggregation of blood platelets which comprisesadministering to a host in need of such inhibition a therapeuticallyeffective amount of a compound of claim
 5. 22. A method of inhibitingthe aggregation of blood platelets which comprises administering to ahost in need of such inhibition a therapeutically effective amount of acompound of claim
 6. 23. A method of inhibiting the aggregation of bloodplatelets which comprises administering to a host in need of suchinhibition a therapeutically effective amount of a compound of claim 7.24. A method of inhibiting the aggregation of blood platelets whichcomprises administering to a host in need of such inhibition atherapeutically effective amount of a compound of claim
 8. 25. A methodof treating thrombosis, inflammation, bone degradation, tumor,mttastasis, or a cell aggregation-related condition which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 1. 26. A method of treatingthrombosis, inflammation, bone degradation, tumor, metastasis, or a cellaggregation-related condition which comprises administering to a host inneed of such treatment a therapeutically effective amount of a compoundof claim
 2. 27. A method of treating thrombosis, inflammation, bonedegradation, tumor, metastasis, or a cell aggregation-related conditionwhich comprises administering to a host in need of such trea,ment atherapeutically effective amount of a compound of claim
 3. 28. A methodof treating thrombosis, inflammation, bone degradation, tumor,metastasis, or a cell aggregation-related condition which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 4. 29. A method of treatingthrombosis, inflammation, bone degradation, tumor, metastasis, or a cellaggregation-related condition which comprises administering to a host inneed of such treatment a therapeutically effective amount of a compoundof claim
 5. 30. A method of treating thrombosis, inflammation, bonedegradation, tumor, metastasis, or a cell aggregation-related conditionwhich comprises administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 6. 31. A methodof treating thrombosis, inflammation, bone degradation, tumor,metastasis, or a cell aggregation-related condition which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 7. 32. A method of treatingthrombosis, inflammation, bone degradation, tumor, metastasis, or a cellaggregation-related condition which comprises administering to a host inneed of such treatment a therapeutically effective amount of a compoundof claim
 8. 33. A method of treating thromboembolic disorders selectedfrom thrombus or embolus formation, harmful platelet aggregation,reocclusion following thrombolysis, reperfusion injury, restenosis,atherosclerosis, stroke myocardial infarction, and unstable angina,which comprises administering to a host in need of such treatment atherapeutically effective amount of a compound of claim
 1. 34. A methodof treating thromboembolic disorders selected from thrombus or embolusformation, harmful platelet aggregation, reocclusion followingthrombolysis, reperfusion injury, restenosis, atherosclerosis, strokemyocardial infarction, and unstable angina, which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 2. 35. A method of treatingthromboembolic disorders selected from thrombus or embolus formation,harmful platelet aggregation, reocclusion following thrombolysis,reperfusion injury, restenosis, atherosclerosis, stroke myocardialinfarction, and unstable angina, which comprises administering to a hostin need of such treatment a therapeutically effective amount of acompound of claim
 4. 36. A method of treating thromboemnbolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering to a host in need of suchtreatment a therapeutically effective amount of a compound of claim 5.37. A method of treating thromboembolic disorders selected from thrombusor embolus formation, harmful platelet aggregation, reocclusionfollowing thrombolysis, reperfusion injury, restenosis, atherosclerosis,stroke myocardial infarction, and unstable angina, which comprisesadministering to a host in need of such treatment a therapeuticallyeffective amount of a compound of claim
 6. 38. A method of treatingthromboembolic disorders selected from thrombus or embolus formation,harmful platelet aggregation, reocclusion following thrombolysis,reperfusion injury, restenosis, atherosclerosis, stroke myocardialinfarction, and unstable angina, which comprises administering to a hostin need of such treatment a therapeutically effective amount of acompound of claim
 7. 39. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering to a host in need of suchtreatment a therapeutically effective amount of a compound of claim 8.40. A method of treating thromboembolic disorders selected from thrombusor embolus formation, harmful platelet aggregation, reocclusionfollowing thrombolysis, reperfusion injury, restenosis, atherosclerosis,stroke myocardial infarction, and unstable angina, which comprisesadministering, in combination, to a host in need thereof atherapeutically effective amount of: (a) a compound of claim 1; and, (b)at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 41. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering, in combination, to a host in needthereof a therapeutically effective amount of: (a) a compound of claim2; and, (b) at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 42. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering, in combination, to a host in needthereof a therapeutically effective amount of: (a) a compound of claim3; and, (b) at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 43. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering, in combination, to a host in needthereof a therapeutically effective amount of: (a) a compound of claim4; and, (b) at least one compound selected from the group consisting ofanti-coagulants;, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 44. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering, in combination, to a host in needthereof a therapeutically effective amount of: (a) a compound of claim5; and, (b) at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 45. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering, in combination, to a host in needthereof a therapeutically effective amount of: (a) a compound of claim6; and, (b) at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 46. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenosis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering, in combination, to a host in needthereof a therapeutically effective amount of: (a) a compound of claim7; and, (b) at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 47. A method of treating thromboembolic disordersselected from thrombus or embolus formation, harmful plateletaggregation, reocclusion following thrombolysis, reperfusion injury,restenossis, atherosclerosis, stroke myocardial infarction, and unstableangina, which comprises administering, in combination, to a host in needthereof a therapeutically effective amount of: (a) a compound of claim8; and, (b) at least one compound selected from the group consisting ofanti-coagulants, anti-platelet agents, thrombin inhibitors, andthrombolytic agents.
 48. A method of treating rheumatoid arthritis,asthma, allergy, adult respiratory distress syndrome, graft versus hostdisease, organ transplantation, septic shock, psoriasis, eczema, contactdermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis,wound healing, diabetic retinopathy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim1.
 49. A method of treating rheumatoid arthritis, asthma, allergy, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim2.
 50. A method of treating rheumatoid arthritis, asthma, allergy, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim3.
 51. A method of treating rheumatoid arthritis, asthma, allergy, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim4.
 52. A method of treating rheumatoid arthritis, asthma, allergy, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopat~hy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim5.
 53. A method of treating rheumatoid arthritis, asthma, allergy, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim6.
 54. A method of treating rheumatoid arthritis, asthma, allergy, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim7.
 55. A method of treating rheumatoid arthritis, asthma, allergy, adultrespiratory distress syndrome, graft versus host disease, organtransplantation, septic shock, psoriasis, eczema, contact dermatitis,osteoporosis, osteoarthritis, atherosclerosis, metastasis, woundhealing, diabetic retinopathy, inflammatory bowel disease or otherautoimmune disease which comprises administering to a host in need ofsuch treatment a therapeutically effective amount of a compound of claim8.